Carbamoyl-type benzofuran derivatives

ABSTRACT

The present invention provides a carbamoyl-type benzofuran derivative of the formula [1]:  
                 
 
wherein Ring Z is a group of the formula:  
                 
 
etc.; A is a single bond, and the like; Y is a cycloalkanediyl group, etc.; R 4  and R 5  are the same or different and each is an optionally substituted lower alkyl group, etc.; R 1  is a halogen atom, etc.; Ring B of the formula:  
                 
 
is an optionally substituted benzene ring; and R 3  is a hydrogen atom. etc., or a pharmaceutically acceptable salt thereof, which is useful as an FXa inhibitor.

TECHNICAL FIELD

The present invention relates to carbamoyl-type benzofuran derivativesuseful as a medicament, particularly as an inhibitor of activated bloodcoagulation factor X (hereinafter, referred to as “FXa”), orpharmaceutically acceptable salt thereof.

BACKGROUND ART

In late years, as the westernization of living habit and the aging ofpopulations, thromboembolic diseases such as myocardial infarction,cerebral infarction and peripheral arterial thrombosis increase year byyear, and social importance of treatment thereof has risen more andmore.

Among therapies of thromboembolic diseases, anticoagulant therapy, aswell as fibrinolytic therapy and antiplatelet therapy, takes part inmedical therapy for treatment and prevention of thrombosis (Sogorinsho41: 2141-2145, 1989). In particular, the safety sustainable to chronicadministration and the reliable and appropriate expression ofanticoagulant activity are essential in the prevention of thrombosis. Acoumarin derivative, especially warfarin potassium, has often been usedall over the world as an anticoagulant available orally. However, owingto the characteristics arisen from the mechanism of action, it requireslong time until the drug efficacy manifests and has very long half-lifein blood, although the concentration range for expression of drugefficacy is relatively narrow, and also shows significant differences inthe effective dose among individuals. For these reasons, theanticoagulant ability can hardly be controlled (Journal of ClinicalPharmacology, 1992, vol. 32, pp. 196-209; NEW ENGLAND JOURNAL OFMEDICINE, 1991, vol. 324, no. 26, pp. 1865-1875). In addition, there maybe adverse drug reactions such as risk of bleeding, nausea, vomiting,diarrhea, depilation, and the like, and therefore the clinicalapplication thereof is very difficult and the development ofanticoagulants that are useful and easy to handle has been demanded.

Furthermore, enhancement of blood clotting ability is one of significantcausative factors of unstable angina, cerebral infarction, cerebralembolism, myocardial infarction, pulmonary infarction, pulmonaryembolism, Buerger's disease, deep vein thrombosis, disseminatedintravascular coagulation, thrombogenesis after artificial heart valvedisplacement, reocclusion after blood circulation reconstruction andthrombogenesis during extracorporeal circulation, and the likeTherefore, a distinguished anticoagulant that shows good dose responseand lower risk of hemorrhage with few side-effects, and can exertsufficient effects by oral administration has been desired (ThrombosisResearch, 1992, vol. 68, pp. 507-512).

Thrombin participates not only in the conversion of fibrinogen tofibrin, which is the final stage of the coagulation cascade, but alsodeeply in the activation and aggregation of blood platelets (Matsuo, O.,“t-PA and Pro-UK”, Gakusaikikaku, 1986, pp. 5-40), and an inhibitorthereof has long been the center of the research in anticoagulants as atarget of development of new drugs. However, a thrombin inhibitor showslow bioavailability upon oral administration and also has drawbacks inregard to safety such as bleeding tendency as one of side effects(Biomedica Biochimica Acta, 1985, Vol. 44, p. 1201-1210).

FXa is a key enzyme located in the position of the common pathway ofboth extrinsic and intrinsic coagulation cascade reactions. FXa islocated upstream from thrombin in the coagulation cascade. Therefore,the inhibition of FXa is possibly more effective and specific in theinhibition of coagulation system compared to the inhibition of thrombin(Thrombosis Research, 1980, Vol. 19, pp. 339-349).

Thus, a substance which inhibits FXa and shows distinguished enzymeselectivity and high bioavailability is expected to undergo control ofits anticoagulant activity for a long period of time and can expresssuperior therapeutic effect upon oral administration compared to theexisting anticoagulants. Accordingly, the development of a novel FXainhibitor adapted to oral administration has been earnestly demanded.

Examples of known compounds having inhibitory effect on FXa includethiobenzamide compounds that are useful in prevention or treatment ofthrombosis (WO99/42439).

The following benzofuran compounds have also been known (Indian Journalof Hetero Cyclic Chemistry, 1994, Vol. 3, pp. 3247-3252), but saidliterature does not mention about the inhibitory effect of the compoundson FXa.

Condensed bicyclic amide compounds of the formula:

which has an activity of suppressing the growth of activated lymphocytesand are useful as a drug for preventing or treating autoimmune diseasesare also known (WO02/12189). The WO02/12189 does not mention about theinhibitory effect on FXa either. In the pamphlet, compounds having acondensed ring of pyridine and furan to which ring an amide and acarbamoyl groups are di-substituted are disclosed; however, saidcompounds all have a benzene ring on the nitrogen atom of the carbamoylgroup, said benzene ring being substituted by X and Y simultaneously.

DISCLOSURE OF INVENTION

The present invention provides a novel carbamoyl-type benzofuranderivative having excellent inhibitory effect on FXa, orpharmaceutically acceptable salts thereof.

The present inventors have intensively studied and have found that acarbamoyl-type benzofuran derivative of the formula below has anexcellent FXa-inhibiting activity and advantageous features that enablecontrolling anticoagulant activity for a long period of time upon oraladministration, and established the present invention.

That is, the present invention is as follows:

1. A carbamoyl-type benzofuran derivative of the formula [1]:

wherein Ring Z is a group of the formula:

A is a single bond or a group of the formula: —NH—;

Y is a lower alkylene group, a cycloalkanediyl group, a phenyl group ora saturated heterocyclic group;

R⁴ and R⁵ are the same or different and each is a hydrogen atom, anoptionally substituted lower alkyl group or an optionally substitutedsaturated heterocyclic group, or R⁴ and R⁵ combine together at the endsto form an optionally substituted nitrogen-containing saturatedheterocyclic group along with the adjacent nitrogen atom;

R¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkoxy group, a cyano group, or an amino group optionally substituted by1 to 2 lower alkyl groups; Ring B of the formula:

is an optionally substituted benzene ring; and

R³ is a hydrogen atom or a lower alkyl group, or a pharmaceuticallyacceptable salt thereof.

2. The compound according to 1 above, wherein Ring Z is a group of theformula:

3. The compound according to 2 above, wherein the “optionallysubstituted lower alkyl group” for R⁴ or R⁵ is an unsubstituted loweralkyl group, a lower alkyl group substituted by an amino groupoptionally substituted by 1 to 2 lower alkyl groups, a lower alkyl groupsubstituted by a hydroxyl group, a lower alkyl group substituted by alower alkoxy group or a lower alkyl group substituted by a pyridylgroup;

the “optionally substituted saturated heterocyclic group” for R⁴ or R⁵is tetrahydropyranyl;

the “optionally substituted nitrogen-containing saturated heterocyclicgroup” formed from R⁴, R⁵ and the adjacent nitrogen atom, when R⁴ and R⁵combine together at the ends, is a pyrrolidinyl group, a morpholinylgroup, a pyrrolidinyl group substituted by a hydroxy-lower alkyl group,a pyrrolidinyl group substituted by a hydroxyl group, a thiomorpholinylgroup, a piperidyl group, a piperidyl group substituted by a hydroxylgroup, a piperazinyl group substituted by a hydroxy-lower alkyl group, apiperidyl group substituted by a hydroxy-lower alkyl group, apiperazinyl group substituted by a lower alkyl group, a pyrrolidinylgroup substituted by a lower alkoxycarbonylamino group, a piperidylgroup substituted by an amino group optionally substituted by 1 to 2lower alkyl groups, an oxopyrrolidinyl group, an oxomorpholinyl group,an oxothiomorpholinyl group, an oxopiperidyl group, an oxopiperazinylgroup, or a piperidyl group substituted by a lower alkoxycarbonyl group;and

the “saturated heterocyclic group” for Y is a piperidyl group.

4. The compound according to 3 above, wherein Ring B is a benzene ringoptionally substituted by one or two groups selected independently froma halogen atom, an optionally substituted lower alkyl group, a hydroxygroup, an optionally substituted lower alkoxy group, an oxy groupsubstituted by an optionally substituted saturated heterocyclic group, asubstituted carbonyl group, an optionally substituted amino group, anitro group, a cyano group, a 4,5-dihydroxazolyl group and a group ofthe formula:

5. The compound according to 4 above, wherein the “optionallysubstituted lower alkyl group” as a substituent for Ring B is a loweralkyl group optionally substituted by a group selected from thefollowings:

(1) a lower alkoxycarbonyl group,

(2) a carboxyl group,

(3) a carbamoyl group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c)a hydroxy-lower alkyl group, (d) an aminoalkyl group optionallysubstituted by 1 to 2 lower alkyl groups, and (e) a lower alkoxy group,

(4) a carbonyl group substituted by a morpholinyl group,

(5) a piperidylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(6) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(7) a carbonyl group substituted by a hydroxyl group-substitutedpiperidyl group,

(8) a hydroxyl group, and

(9) a pyrrolidinylcarbonyl group;

the “optionally substituted lower alkoxy group” as a substituent forRing B is a lower alkoxy group optionally substituted by a groupselected from the followings:

(1) a carboxyl group,

(2) a lower alkoxycarbonyl group,

(3) a lower alkoxy group,

(4) a hydroxyl group,

(5) an aminooxy group optionally substituted by 1 to 2 loweralkoxycarbonyl groups,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a group selected from morpholinylgroup, a piperidyl group or a pyrrolidinyl group,

(8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(11) a carbonyl group substituted by a lower alkyl-piperazinyl group,

(12) an amino group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c)a lower alkanoyl group,

(13) a carbamoyl group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c)a hydroxy-lower alkyl group, and (d) a lower alkyl group substituted byan amino group optionally substituted by 1 to 2 lower alkyl groups; and

(14) a group of the formula: —O—NH—C(═NH)NH₂;

the “oxy group substituted by an optionally substituted saturatedheterocyclic group” as a substituent for Ring B is an oxy groupsubstituted by a saturated heterocyclic group optionally substituted byan aromatic hydrocarbon group;

the “substituted carbonyl group” as a substituent for Ring B is acarbonyl group substituted by a group selected from the followings:

(1) a lower alkoxy group,

(2) a hydroxyl group,

(3) an amino group optionally substituted by 1 to 2 groups selected from(a) a lower alkyl group, (b) a lower alkoxy group, (c) a loweralkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a loweralkyl group substituted by an amino group optionally substituted by 1 to2 lower alkyl groups, (f) a lower alkyl group substituted by an aromatichydrocarbon group, and (g) a lower alkyl group substituted by a pyridylgroup,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or athiomorpholinyl group,

(5) a hydroxypiperidyl group,

(6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinyl group;

the “optionally substituted amino group” as a substituent for Ring B isan amino group optionally substituted by 1 to 2 groups selected from thefollowings:

(1) a lower alkyl group,

(2) a lower alkoxy-lower alkyl group,

(3) a hydroxy-lower alkyl group,

(4) a lower alkanoyl group,

(5) a lower alkoxy-lower alkanoyl group,

(6) a hydroxy-lower alkanoyl group,

(7) a lower alkanoyl group substituted by a lower alkanoyloxy group,

(8) a lower alkanoyl group substituted by an amino group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl group and(b) a lower alkanoyl group,

(9) a lower alkoxycarbonyl group,

(10) a lower alkoxycarbonyl group substituted by an aromatic hydrocarbongroup,

(11) a carbamoyl group substituted by 1 to 2 lower alkyl groups,

(12) a lower alkylsulfonyl group, and

(13) a lower alkylsulfonyl group substituted by a morpholinyl group.

6. The compound according to 5 above, wherein Ring B is an unsubstitutedbenzene ring.

7. The compound according to 5 above, wherein Ring Z is a group of theformula:

the formula:

R¹ is a halogen atom or a lower alkyl group;

R² is a group selected from the followings:

A) a hydrogen atom, a cyano group, an amino group optionally substitutedby 1 to 2 lower alkyl groups, a hydroxy group;

B) a lower alkyl group optionally substituted by a group selected fromthe followings:

(1) a lower alkoxycarbonyl group,

(2) a carboxyl group,

(3) a carbamoyl group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c)a lower alkyl group substituted by a hydroxyl group, (d) a lower alkylgroup substituted by an amino group optionally substituted by 1 to 2lower alkyl groups, and (e) a lower alkoxy group,

(4) a carbonyl group substituted by a morpholinyl group,

(5) a piperidylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(6) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(7) a carbonyl group substituted by a hydroxyl group-substitutedpiperidyl group,

(8) a hydroxyl group; and

(9) a pyrrolidinylcarbonyl group;

C) a lower alkoxy group optionally substituted by a group selected fromthe followings:

(1) a carboxyl group,

(2) a lower alkoxycarbonyl group,

(3) a lower alkoxy group,

(4) a hydroxyl group,

(5) an aminooxy group optionally substituted by 1 to 2 loweralkoxycarbonyl groups,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a group selected from a morpholinylgroup, a piperidyl group or a pyrrolidinyl group,

(8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkylgroup,

(11) a carbonyl group substituted by a lower alkyl-piperazinyl group,

(12) an amino group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and(c) alower alkanoyl group,

(13) a carbamoyl group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c)a lower alkyl group substituted by a hydroxyl group, and (d) a loweralkyl group substituted by an amino group optionally substituted by 1 to2 lower alkyl groups, and

(14) a group of the formula: —O—NH—C(═NH)NH₂; or

D) a carbonyl group substituted by a group selected from the followings:

(1) a lower alkoxy group,

(2) a hydroxyl group,

(3) an amino group optionally substituted by 1 to 2 groups selected from(a) a lower alkyl group, (b) a lower alkoxy group, (c) a loweralkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a loweralkyl group substituted by an amino group optionally substituted by 1 to2 lower alkyl groups, (f) a lower alkyl group substituted by an aromatichydrocarbon group, and (g) a lower alkyl group substituted by a pyridylgroup,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or athiomorpholinyl group,

(5) a hydroxypiperidyl group,

(6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinyl group;

A is a single bond; and

R³ is a hydrogen atom.

8. The compound according to 7 above, wherein R² is a group selectedfrom the followings:

(1) a hydrogen atom,

(2) a cyano group,

(3) an amino group optionally substituted by 1 to 2 lower alkyl groups,

(4) a hydroxyl group,

(5) a lower alkoxy group,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a lower alkoxy group substituted by a hydroxyl group,

(8) a lower alkoxy group substituted by an amino group optionallysubstituted by 1 to 2 lower alkyl groups,

(9) a lower alkoxycarbonyl group,

(10) a carboxyl group,

(11) a carbonyl group substituted by an amino group optionallysubstituted by 1 to 2 groups selected from (a) lower alkyl group, (b) ahydroxy-lower alkyl group, (c) a lower alkoxy-lower alkyl group, and (d)a lower alkyl group substituted by an amino group optionally substitutedby 1 to 2 lower alkyl groups,

(12) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, apiperidylcarbonyl group or a thiomorpholinyl-carbonyl group,

(13) a piperidylcarbonyl group substituted by a hydroxy-lower alkylgroup, or a pyrrolidinylcarbonyl group substituted by a hydroxy-loweralkyl group,

(14) a lower alkyl group,

(15) a lower alkyl group substituted by a lower alkoxycarbonyl group,

(16) a carboxy-lower alkyl group,

(17) a lower alkyl group substituted by a carbamoyl group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl group, (b)a hydroxy-lower alkyl group, (c) a lower alkoxy-lower alkyl group, and(d) a lower alkyl group substituted by an amino group optionallysubstituted by 1 to 2 lower alkyl groups,

(18) a lower alkyl group substituted by a morpholinylcarbonyl group,

(19) a lower alkyl group substituted by a piperidylcarbonyl groupsubstituted by a hydroxy-lower alkyl group, or a lower alkyl groupsubstituted by a pyrrolidinylcarbonyl group substituted by ahydroxy-lower alkyl group,

(20) a hydroxy-lower alkyl group, and

(21) a lower alkyl group substituted by a pyrrolidinyl-carbonyl group.

9. The compound according to 7 above, wherein R² is a group selectedfrom the followings:

(1) a hydrogen atom,

(2) a carbonyl group substituted by an amino group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl group and(b) a lower alkoxy-lower alkyl group,

(3) a lower alkoxycarbonyl group,

(4) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, apiperidylcarbonyl group or a thiomorpholinyl-carbonyl group,

(5) a lower alkyl group substituted by a carbamoyl group substituted by1 to 2 lower alkyl groups,

(6) a carboxy-lower alkyl group,

(7) a lower alkyl group substituted by a morpholinylcarbonyl group,

(8) a hydroxy-lower alkyl group,

(9) a lower alkyl group substituted by a pyrrolidinyl-carbonyl group,and

(10) a lower alkyl group substituted by a carbamoyl group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl groupsubstituted by an amino group optionally substituted by 1 to 2 loweralkyl groups and (b) lower alkyl group.

10. The compound according to 7 above, wherein R² is a group selectedfrom the followings:

(1) a hydrogen atom,

(2) a hydroxy-lower alkyl group,

(3) a carboxy-lower alkyl group,

(4) a lower alkoxy group substituted by a lower alkoxy group;

(5) a carbonyl group substituted by a group selected from (a) an aminogroup optionally substituted by 1 to 2 lower alkyl groups, and (b) amorpholinyl group;

(6) a carbamoyl group substituted by 1 to 2 groups selected from (a) alower alkoxy-lower alkyl group and (b) a lower alkyl group;

(7) a lower alkyl group substituted by a carbamoyl group substituted by1 to 2 groups selected from (a) a lower alkoxy-lower alkyl group and (b)a lower alkyl group;

(8) a carbamoyl group substituted by 1 to 2 groups selected from (a) alower alkyl group substituted by an amino group optionally substitutedby 1 to 2 alkyl groups and (b) a lower alkyl group,

(9) a lower alkyl group substituted by a carbamoyl group substituted by1 to 2 groups selected from (a) an amino-lower alkyl group optionallysubstituted 1 to 2 alkyl groups and (b) a lower alkyl group,

(10) a lower alkyl group substituted by a pyrrolidinyl-carbonyl group;and

(11) a carbamoyl-lower alkyl group optionally substituted by 1 to 2groups selected from (a) a lower alkyl group substituted by an aminogroup optionally substituted by 1 to 2 lower alkyl groups and (b) alower alkyl group.

11. A compound of the formula:

wherein X is a group of the formula: —N═ or —CH═;

A is a single bond or a group of the formula: -NH-;

Y is a lower alkylene group, a cycloalkanediyl group, a phenyl group ora saturated heterocyclic group;

R⁶ is a protecting group for carboxyl group;

R¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkoxy group, a cyano group, or an amino group optionally substituted by1 to 2 lower alkyl groups;

Ring B of the formula:

is an optionally substituted benzene ring; and

R³ is a hydrogen atom or a lower alkyl group.

12. A compound of the formula:

wherein X is a group of the formula: —N═ or —CH═;

A is a single bond or a group of the formula: —NH—;

Y is a lower alkylene group, a cycloalkanediyl group, a phenyl group ora saturated heterocyclic group;

R¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkoxy group, a cyano group, or an amino group optionally substituted by1 to 2 lower alkyl groups;

Ring B of the formula:

is an optionally substituted benzene ring; and R³ is a hydrogen atom ora lower alkyl group.

13. The compound according to 11 or 12 above, wherein the formula:

14. The compound according to 5 above, wherein Ring Z is a group of theformula:

R¹ is a halogen atom;

R³ is a hydrogen atom; the formula:

R² is a carbonyl group substituted by a group selected from thefollowings:

(1) a lower alkoxy group,

(2) a hydroxyl group,

(3) an amino group optionally substituted by 1 to 2 groups elected from(a) a lower alkyl group, (b) a lower alkoxy group, (c) a loweralkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a loweralkyl group substituted by an amino group optionally substituted by 1 to2 lower alkyl groups, (f) a lower alkyl group substituted by an aromatichydrocarbon group, and (g) a lower alkyl group substituted by a pyridylgroup,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or athiomorpholinyl group,

(5) a hydroxypiperidyl group,

(6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinyl group;

A is a single bond;

Y is a cyclohexanediyl group; and

R⁴ and R⁵ are independently a lower alkyl group, or R⁴, R⁵ and theadjacent nitrogen atom, when R⁴ and R⁵ combine together at the ends,form a pyrrolidinyl group, a morpholinyl group, a pyrrolidinyl groupsubstituted by a hydroxy-lower alkyl group, a pyrrolidinyl groupsubstituted by a hydroxyl group, a thiomorpholinyl group, a piperidylgroup, a piperidyl group substituted by a hydroxyl group, a piperazinylgroup substituted by a hydroxy-lower alkyl group, a piperidyl groupsubstituted by a hydroxy-lower alkyl group, a piperazinyl groupsubstituted by a lower alkyl group, a pyrrolidinyl group substituted bya lower alkoxycarbonylamino group, a piperidyl group substituted by anamino group optionally substituted by 1 to 2 lower alkyl groups, anoxopyrrolidinyl group, an oxomorpholinyl group, an oxothiomorpholinylgroup, an oxopiperidyl group, an oxopiperazinyl group, or a piperidylgroup substituted by a lower alkoxycarbonyl group.

15. The compound according to 14 above, wherein R² is a carbonyl groupsubstituted by a group selected from the followings:

(1) an amino group optionally substituted by 1 to 2 groups selected from(a) a lower alkyl group, (b) a lower alkoxy group, (c) a loweralkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a loweralkyl group substituted by an amino group optionally substituted by 1 to2 lower alkyl group, (f) a lower alkyl group substituted by an aromatichydrocarbon group, and (g) a lower alkyl group substituted by a pyridylgroup, and

(2) a morpholin-4-yl group, a pyrrolidin-1-yl group, a piperidin-1-ylgroup a piperazin-1-yl group or a thiomorpholin-4-yl group;

R⁴ and R⁵ are independently a lower alkyl group, or

R⁴, R⁵ and the adjacent nitrogen atom, when R⁴ and R⁵ combine togetherat the ends, form a pyrrolidin-4-yl group.

16. The compound according to 15 above, wherein the formula:

R² is a carbonyl group substituted by a group selected from thefollowings:

(1) an amino group optionally substituted by 1 to 2 groups selected from(a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group, and

(2) a morpholin-4-yl group.

17. Methyl2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}-carbonyl)amino]benzofuran-5-carboxylate;

Methyl[2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbonyl}-amino)benzofuran-5-yl]acetate;

N²-(5-Chloropyriclin-2-yl)-N⁵,N⁵-dimethyl-3-({[trans-4-(morpholin-4-ylcarbonyl)cyclohexyl]carbonyl}amino)-benzofuran-2,5-dicarboxamide;

N-(5-Chloropyridin-2-yl)-3-[(5-morpholin-4-yl-5-oxopentanoyl)amino]benzofuran-2-carboxamide;

2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylicacid;

N²-(5-Chloropyridin-2-yl)-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-N⁵,N⁵-dimethylbenzofuran-2,5-dicarboxamide;

trans-N′-[2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-5-(morpholin-4-ylcarbonyl)benzofuran-3-yl]-N,N-dimethyl-cyclohexane-1,4-dicarboxamide,or a pharmaceutically acceptable-salt thereof.

18. A pharmaceutical composition, which comprises as an activeingredient a compound according to any one of 1 to 17 above, or apharmaceutically acceptable salt thereof.

19. A method for treatment of thrombosis, which comprises administeringan effective amount of a compound according to any one of 1 to 17 above,or a pharmaceutically acceptable salt thereof, to a patient in needthereof.

20. Use of a compound according to any one of 1 to 17 above, or apharmaceutically acceptable salt thereof, to a patient in need thereofin treatment of patients suffering from thrombosis.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound [1] of the present invention will be hereinafter describedin detail.

The term “lower” used in the definition of the formulas herein describedmeans unless otherwise noted a straight- or branched-carbon chain having1 to 6 carbon atoms.

Thus, examples of “lower alkyl group” include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methyl-propyl, and the like. Amongthem, alkyl groups having 1 to 4 carbon atoms, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl arecommonly used.

The term “lower alkoxy group” means a substituent wherein an oxygen atomis bound to the above-mentioned alkyl group. Among them, alkoxy groupshaving 1 to 4 carbon atoms, for example, and methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups arecommonly used.

Examples of “lower alkylene group” include a straight- or branched-chainalkylene group having 1 to 6 carbon atoms, specifically, methylene,ethylene, trimethylene, tetra-methylene, pentamethylene, hexamethylene,and the like. Among them, an alkylene group having 1 to 5 carbon atomsis commonly used.

Examples of “lower alkanoyl group” include alkanoyl groups formed byremoving a “OH” group from the carboxyl group of a lower carboxylicacid. Specifically, formyl, acetyl, propionyl, butyryl, and the like arecommonly used.

The “saturated heterocyclic group” means a saturated heterocyclic groupcontaining 1 to 4 hetero atoms selected independently from the groupconsisting of nitrogen atom, oxygen atom and sulfur atom, preferably a4- to 14-membered heterocyclic group containing 1 to 4 hetero atomsselected independently from the group consisting of nitrogen atom,oxygen atom and sulfur atom, including condensed rings. Specificexamples include imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, homopiperazinyl, homopiperidyl,pyrrolidinyl, oxazolidinyl, 1,3-dioxanyl, and the like. Above all,piperidyl, piperazinyl, homopiperazinyl, pyrrolidinyl and morpholinylare commonly used. Further, they are used as a divalent group when usedfor the group: Y.

The “nitrogen-containing saturated heterocyclic group” means a saturatedring containing 1 to 4 hetero atoms, which ring may contain, in additionto nitrogen atom, oxygen atom and/or sulfur atom, preferably, a 4 to14-membered saturated heterocyclic group containing, as hetero atom,only nitrogen atom or both nitrogen atom and oxygen atom, includingcondensed rings. Examples thereof include imidazolidinyl, pyrazolidinyl,piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl,homopiperidyl, pyrrolidinyl, oxazolidinyl, and the like, specifically,piperidyl, piperazinyl, homopiperazinyl, pyrrolidinyl, and morpholinylare commonly used.

Examples of “halogen atom” include fluorine, chlorine, bromine or iodineatom. Above all, fluorine, chlorine or bromine atom is commonly used.

Examples of “cycloalkanediyl group” include 3- to 7-memberedcycloalkanediyl group such as 1,4-cyclohexanediyl group.

Examples of “aromatic hydrocarbon group” include phenyl group andnaphthyl group, and phenyl group is commonly used.

The pharmaceutically acceptable salt of the compound [1] includes a saltwith an inorganic acid such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; a salt with an organic acid such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and thelike; salt with an acidic amino acid such as aspartic acid, glutamicacid, and the like; salt with a metal such as sodium, potassium,magnesium, calcium, aluminium, and the like; salt with an organic basesuch as methylamine, ethylamine, ethanolamine, and the like; or a saltwith a basic amino acid such as lysine, ornithine, and the like.

The compound [1] of the present invention can be in the form ofquaternary ammonium salt and such a quaternary ammonium salt fallswithin the scope of the present compound [1].

Further, the compound [1] of the present invention includes anintramolecular salt, hydrate, solvate or crystalline polymorphism, andthe like.

Besides, when the compound [1] has an asymmetric carbon atom(s), it canexist as an optical isomer, and the present invention encompass thoseisomers and a mixture thereof. Further, when the compound [1] has adouble bond and/or a ring to which a cycloalkanediyl group having two ormore substituents is attached, it may exist in the form of cis or trans,and the present invention encompass those isomers and a mixture thereof.

Additionally, the compound [1] of the present invention encompasses aprodrug of a compound as mentioned above. Examples of a prodrug includethose prepared by protecting a functional group such as an amino orcarboxy group of a compound [1] above with a conventional protectinggroup.

The compound of the present invention may be prepared by the followingprocesses.

[Process A]

Among the compounds [1] of the present invention, a compound wherein Ais a single bond, i.e., a compound of the formula [1-A]:

wherein the symbols are the same as defined above can be prepared byreacting an amino compound of the formula [2]:

wherein the symbols are the same as defined above, with a carboxylicacid compound of the formula [3-A1]:HOOC—Y—CO—N(R⁴)(R⁵)   [3-A1]wherein the symbols are the same as defined above, or a reactivederivative thereof at its carboxyl group.[Process B]

The compound [1-A] can also be prepared by reacting the compound [2]with a compound of the formula [3-A2]:HOOC—Y—COOR⁶   [3-A2]wherein R⁶ is a protecting group for carboxyl group and the other symbolis the same as defined above, or a reactive derivative thereof at itscarboxyl group, to give a compound of the formula [2-A1]:

wherein the symbols are the same as defined above, removing theprotecting group for carboxyl group to give a compound of the formula[2-A2]:

wherein the symbols are the same as defined above, and reacting thecompound [2-A2] with a compound of the formula: [3-A3]:HN(R⁴) (R⁵)   [3-A3]wherein the symbols are the same as defined above.[Process C]

Among the compounds [1] of the present invention, those wherein A is agroup of the formula: —NH—, i.e., a compound of the formula [1-B]:

wherein the symbols are the same as defined above can be prepared byreacting the above-mentioned compound [2] with a compound of the formula[3-B1]:H₂N—Y—COOR⁶   [3-B 1]wherein the symbols are the same as defined above and a compound of theformula [3-B2]:L¹—CO—L²   [3-B2]wherein L¹ and L² are the same or different and each a leaving group togive a compound of the formula [2-B1]:

wherein the symbols are the same as defined above, removing theprotecting group for carboxyl group to give a compound of the formula[2-B2]:

wherein the symbols are the same as defined above, and reacting thecompound [2-B2] with the compound [3-A3].

The compound [1] can also be prepared, if necessary, through the mutualconversion, wherein a substituent(s) of resulting compound [1-A] or[1-B] is adequately converted into a compound [1] through the mutualconversion by alkylation, reductive alkylation, amidation,sulfonyl-amidation, reduction, dealkylation, hydrolysis, quaternaryamination, formylation, protection or deprotection of amino or carboxylgroup, and the like.

[Manufacturing Process for Starting Materials: Preparation of compound[2]]

The compound [2] can be prepared by a process comprising:

converting the aldehyde group of a compound of the formula [10]:

wherein the symbols are the same as defined above, into cyano group togive a compound of the formula [9]:

wherein the symbols are the same as defined above, reacting the compound[9] with a compound of the formula [8]:

wherein L³ is a leaving group and P¹ is a protecting group for carboxylgroup, to give a compound of the formula [7]:

wherein the symbols are the same as defined above, removing theprotecting group P¹ of the compound [7] to give a compound of theformula [6]:

wherein the symbols are the same as defined above, reacting the compound[6], if necessary, after converting into a reactive derivative at thecarboxyl group thereof, with a compound of the formula [5]:

wherein the symbols are the same as defined above, to give a compound ofthe formula [4]:

wherein the symbols are the same as defined above, and subjecting thecompound [4] to cyclization.

Further, the compound [4] can be prepared by reacting a compound of theformula [9] with a compound of the formula [12]:

wherein L⁴ is a leaving group and the other symbols are the same asdefined above.

The compound [4] can also be prepared by reacting a compound of theformula [13]:

wherein L⁵ is a leaving group and the other symbols are the same asdefined above with a compound of the formula [14]:

wherein the symbols are the same as defined above.

Further, the compound of the formula [10] can be prepared by formylatinga compound of the formula [11]:

wherein the symbols are the same as defined above.

The Processes [A]-[C] above can be carried out in the following manner.

[Process A]

The reaction where a compound [1-A] is prepared using a compound [2] anda compound [3-A1] or a reactive derivative thereof at its carboxyl groupcan be carried out in a conventional manner for amidation. That is, thereaction can be carried out by reacting a compound [2] with a compound[3-A1] or a reactive derivative thereof, or a salt thereof in thepresence or absence of a condensing agent, and if necessary, in thepresence of an acid scavenger, in an appropriate solvent.

The condensing agent includes conventional agents such asN,N-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or a hydrochloridethereof, carbonyldiimidazole (CDI), diphenylphosphoryl-azide (DPPA),diethyl cyanophosphonate (DEPC), and the like. Above all, DCC, EDC or ahydrochloride thereof is preferred.

Examples of the reactive derivative of the compound [3-A1] include thoseconventionally used such as an acid halide, a mixed anhydride, areactive ester, and the like. Examples of an activator that can be usedfor converting the compound [3-A1] into the reactive derivative thereofinclude thionyl chloride, thionyl bromide, oxalyl chloride,N-hydroxylamines such as 1-hydroxysuccinimide, 1-hydroxybenzotriazole,and the like, and phenols such as p-nitrophenol, and the like. Aboveall, thionyl chloride, oxalyl chloride, 1-hydroxysuccinimide and1-hydroxybenzotriazole are preferred. The acid chloride method isespecially preferable.

Examples of the salt of a compound [3-A1] or a reactive derivative ofthe compound [3-A1] include a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, and the like. Anacid scavenger is also usable depending on the method to be employed,which includes inorganic or organic bases.

The present reaction may be facilitated when it is carried out in thepresence of a base or by using such a base as a solvent. Examples ofinorganic bases include alkali metal carbonates (sodium carbonate,potassium carbonate, cesium carbonate, and the like.), alkali earthmetal carbonates (calcium carbonate, and the like.), alkali metalhydrogen carbonates (sodium hydrogen carbonate, potassium hydrogencarbonate, and the like.), alkali metal hydroxides (sodium hydroxide,potassium hydroxide, lithium hydroxide, and the like). Examples oforganic bases include tri-lower alkylamines (triethylamine,tributylamine, diisopropylethylamine, and the like), tertiary-amines(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]undec-7-ene, and the like), amines(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, andthe like), pyridine, lutidine, collidine, and the like. Above all,triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, orpyridine is preferred for carrying out the reaction. The presentreaction can be carried out in the presence or absence of a solvent,preferably in the presence of a solvent.

Examples of the solvent include any inert solvent which does not disturbthe reaction, such as halogenated hydrocarbons (chloroform,dichloromethane, dichloroethane, and the like), aromatic hydrocarbons(benzene, toluene, xylene, and the like), ethers (diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, andthe like), esters (ethyl acetate, and the like), amides(N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like), nitrites (acetonitrile,and the like), dimethylsulfoxide, pyridine, 2,6-luthidine, and the like,a mixed solvent comprising two or more of these solvents, if necessary,and also a mixture of any one(s) of these solvents and water. It ispreferred to select any appropriate solvent depending on the methodused. Above all, dichloromethane, chloroform, toluene, xylene,tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, pyridine, and the like are preferred,and dichloromethane, chloroform, N,N-dimethylformamide and pyridine areespecially preferred. The present reaction can be carried out in a widerange of temperature from a temperature of under cooling to underheating. For example, the reaction can be preferably carried out at atemperature of −10° C. to the boiling point of the reaction mixture,especially from under ice-cooling to 60° C.

[Process B]

The reaction between the compound [2] and a compound [3-A2] or areactive derivative thereof at the carboxyl group can be carried out ina similar manner to the reaction between the compound [2] and a compound[3-A1] or a reactive derivative thereof at the carboxyl group. Theremoval of a protecting group at the carboxyl group of compound [2-A1]can be carried out in a conventional manner. The next reaction with acompound [3-A3] can be carried out in a similar manner to the reactionbetween the compound [2] and a compound [3-A1].

[Process C]

The process wherein the compound [2-B1] is prepared by reacting acompound [2] with compounds of the formulas [3-B1] and [3-B2] can becarried out in accordance with a conventional method for carbonylationin the presence of an appropriate acid scavenger in an appropriatesolvent.

Examples of a leaving group for a compound of the formula [3-B2] includea halogen atom. Examples of a compound [3-B2] include phosgene,triphosgene, CDI, and the like, and triphosgene is preferred.

Examples of acid scavenger used in the reaction include both theinorganic and organic bases. Examples of inorganic bases include alkalimetal carbonates (sodium carbonate, potassium carbonate, cesiumcarbonate, and the like) and alkali metal hydrogen carbonates (sodiumhydrogen carbonate, potassium hydrogen carbonate, and the like).Examples of organic bases include tri-lower alkylamines (triethylamine,tributylamine, diisopropylethylamine, and the like), tertiary-amines(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]-undec-7-ene, and the like), amines(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, andthe like), pyridine, lutidine, collidine, and the like. Above all,triethylamine, diisopropylethylamine, 4-dimethylaminopyridine andpyridine are preferred.

Examples of the solvent include any inert solvent which does not disturbthe reaction, such as halogenated hydrocarbons (chloroform,dichloromethane, dichloroethane, and the like), ethers (diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, andthe like), esters (ethyl acetate, and the like), amides(N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like), nitriles (acetonitrile,and the like), pyridine, 2,6-luthidine, and the like, and a mixedsolvent comprising two or more of these solvents, if necessary. It ispreferred to select any appropriate solvent depending on the methodused. Above all, dichloromethane, tetrahydrofuran,N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, pyridine, and the like are preferred,and dichloromethane and N,N-dimethylformamide are especially preferred.The present reaction can be carried out in a wide range of temperaturefrom −78° C. to the boiling point of the reaction mixture. For example,the reaction can be preferably carried out at a temperature of −10° C.to the boiling point of the reaction mixture, especially at atemperature of under ice-cooling to room temperature.

The removal of a protecting group at the carboxyl group of compound[2-B1] can be carried out in a conventional manner, for example, byhydrolysis in the presence of an acid such as trifluoroacetic acid, andthe like. The next reaction with a compound [3-A3] can be carried out ina similar manner to the reaction between the compound [2] and a compound[3-A1].

Furthermore, after carrying out the Processes [A], [B], [C], theobjective compound [1] can also be obtained, if necessary, through amutual conversion by conducting the following reaction(s), on conditionthat the resulting compound of the formula [1-A] or [1-B] has one ormore moieties available to further reaction(s) in the substituent(s)(mainly referring to, for example, a protecting group for amine,alcoholic or phenolic OH, ester, carboxylic acid, nitro, halogen, andthe like).

The reactions for amidation, reduction and hydrolysis, among thereactions to be conducted when needed, can be carried out as follows.

The amidation can be carried out in a manner similar to theabove-mentioned reaction between a compound [2] and a compound [3-A1],when needed.

The reduction can be carried out in a conventional manner, when needed.For example, the reaction can be carried out by reacting a compound [1]with an appropriate reducing agent, or with hydrogen in the presence ofa metal catalyst in an appropriate solvent.

In the reaction, any conventional reducing agents can be used withoutlimitation; however, metal hydride reducing agents such as lithiumaluminium hydride, lithium borohydride, sodium borohydride, and thelike, metals such as zinc, iron, stannum, and the like, and metal saltssuch as tin chloride, and the like are preferred, and metals such asstannum, and the like and metal salts such as tin chloride, and the likeare more preferred. In the catalytic hydrogenation, any conventionalmetal catalysts can be used without limitation; however,palladium-carbon, Raney Nickel, Raney Cobalt, platinum oxide, and thelike are preferred and metals such as Raney Nickel, and the like aremore preferred. Furthermore, depending on the method used, the reactioncan sometimes be facilitated when it is carried out under an acidiccondition in the co-existence of a mineral acid such as hydrochloricacid, and the like In the reaction where a metal hydride reducing agentis used, any inert solvents which do not disturb the reaction can beused without limitation, and examples thereof include ethers (diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,and the like), amides (N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like), aromatic hydrocarbons(benzene, toluene, xylene, and the like), alcohols (methanol, ethanol,propanol, and the like), water, and the like, and a mixed solventcomprising two or more of these solvents, if necessary. It is preferredto select any appropriate solvent depending on the method used.

In the reaction where a metal such as zinc, iron, stannum, and the like,or a metal salt such as tin chloride, and the like is used, any inertsolvents which do not disturb the reaction can be used withoutlimitation, and examples thereof include water, alcohols (methanol,ethanol, propanol, and the like), esters (ethyl acetate, and the like),ethers (diethyl ether, diisopropyl ether, tetrahydrofuran,1,2-dimethoxyethane, and the like), amides (N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and the like),nitrites (acetonitrile, and the like), aromatic hydrocarbons (benzene,toluene, xylene, and the like), and a mixed solvent comprising two ormore of these solvents, if necessary. It is preferred to select anyappropriate solvent depending on the method used. Above all, ethylacetate, water, or a mixed solvent comprising water and an alcohol, anether, an amide, a nitrile and the like is preferred.

In the reaction where hydrogenation is carried out in the presence of ametal catalyst, any inert solvents which do not disturb the reaction canbe used without limitation, and examples thereof include alcohols,ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, esters(ethyl acetate, and the like), organic acids (formic acid, acetic acid,propionic acid, trifluoroacetic acid, and the like), and a mixed solventcomprising two or more of these solvents, if necessary. It is preferredto select any appropriate solvent depending on the method used.

The present reaction can be carried out in a wide range of temperaturefrom a temperature of under cooling to under heating. For example, thereaction can be preferably carried out at a temperature of −10° C. tothe boiling point of the reaction mixture.

The hydrogen pressure used in the catalytic hydrogenation reaction isgenerally about 1-100 atm.

The reaction time for the present reaction varies depending on the kindof the reducing agent or the activity of the catalyst used; however, itis generally between is about 10 minutes and 24 hours.

The hydrolysis can be carried out in a conventional manner, when needed.

The protection and deprotection of amino or carboxyl group can becarried out according to any one of known methods, when needed.

The mutual conversion of a compound [1] by alkylation, reductivealkylation, sulfonyl-amidation, dealkylation, quaternary amination,formylation, and the like, can be conducted properly using any one ofknown methods.

[Manufacturing Process for Starting Materials: Preparation of compound[2]]

(1) The reaction for converting the aldehyde group of the compound [10]into a cyano group to give the compound [9] can be carried out byreacting the compound [10] with a hydroxylamine or hydrochloride thereofin the presence or absence of sodium formate in an appropriate solvent.A dehydrating agent may be added. The solvent available includes anorganic lower fatty acid such as formic acid; however, it is preferredto select an appropriate solvent depending on the method used.

The present reaction can be carried out in a wide range of temperaturefrom a temperature of under cooling to under heating. For example, thereaction can be preferably carried out at a temperature of underice-cooling to the boiling point of the reaction mixture, especially atthe boiling point of the reaction mixture.

(2) The next reaction between the resulting compound [9] and thecompound [8] to give the compound [7] can be carried out in aconventional manner for O-alkylation of a phenol compound. The presentreaction can be carried out by reacting the compound [9] with thecompound [8] in an appropriate solvent in the presence of a base or byusing such a base as the solvent.

The leaving group in the compound [8] can be preferably, for example, ahalogen atom. Examples of a preferred protecting group for the carboxylgroup of the compound [8] include a lower alkyl group and a phenyl-loweralkyl group.

Examples of the base usable include both the inorganic and organic basessuch as alkali metal carbonates (sodium carbonate, potassium carbonate,and the like), alkali metal hydrogen carbonates (sodium hydrogencarbonate, potassium hydrogen carbonate, and the like), alkali metalhydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like), alkali metal hydrides (sodium hydride, and the like),alkali metal alkoxides (sodium methoxide, potassium t-butoxide, and thelike), tri-lower alkylamines (triethylamine, tributylamine,diisopropylethylamine, and the like), tertiary-amines(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]-undec-7-ene, and the like), amines(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, andthe like), pyridine, lutidine, collidine, and the like. Above all,alkali metal carbonate, diisopropylethylamine, pyridine, and the likeare preferred.

Examples of the solvent include any inert solvent which does not disturbthe reaction, such as ketones (e.g., acetone, methylethyl ketone, andthe like), aromatic hydrocarbons (benzene, toluene, xylene, and thelike), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, and the like), amides(N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like), nitriles (acetonitrile,and the like), alcohols (methanol, ethanol, propanol, 2-butanol, and thelike), dimethylsulfoxide, pyridine, 2,6-luthidine, and the like, and amixed solvent comprising two or more of these solvents, if necessary.Above all, ketones such as acetone, methylethyl ketone, and the like,and amides such as N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like are preferred.

The present reaction can be carried out in a wide range of temperaturefrom a temperature of under cooling to under heating. For example, thereaction can be preferably carried out at a temperature of underice-cooling to the boiling point of the reaction mixture.

An alkali metal iodide such as lithium iodide, sodium iodide, potassiumiodide, and the like can also be added, which may facilitate thereaction.

(3) The reaction for removing a protecting group from the compound [7]to give the compound [6] can be carried out by a method generally usedfor the deprotection of carboxyl group.

(4) The reaction between the compound [5] and the compound [6) to givethe compound [4] can be carried out in a manner similar to that forreacting the compound [2] with the compound [3-A].

(5) The reaction for cyclizing the compound [4] to give the compound [2]can be carried out by treating the compound [4] with a base in anappropriate solvent.

Examples of the base usable include both the inorganic and organic basessuch as alkali metal carbonates (sodium carbonate, potassium carbonate,and the like), alkali metal hydroxides (sodium hydroxide, potassiumhydroxide, lithium hydroxide, and the like), alkali metal hydrides(sodium hydride, and the like), alkali metal alkoxides (sodiummethoxide, potassium t-butoxide, and the like), tri-lower alkylamines(triethylamine, tributylamine, diisopropylethylamine, and the like),tert-amines (1,4-diazabicyclo[2.2.2]octane,1,5-diazabicyclo[4.3.0]-non-5-ene, 1,8-diazabicyclo[5.4.0)undec-7-ene,and the like), amines (N,N-dimethylaniline, N,N-diethylaniline,4-dimethylaminopyridine, and the like), pyridine, lutidine, collidine,and the like.

The present reaction can be carried out in the presence or absence of asolvent, preferably in the presence of a solvent. Examples of thesolvent include any inert solvent which does not disturb the reaction,such as aromatic hydrocarbons (benzene, toluene, xylene, and the like),ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, and the like), amides (N,N-dimethylformamide,N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, and the like),nitrites (acetonitrile, and the like), alcohols (methanol, ethanol,propanol, 2-butanol, and the like), dimethylsulfoxide, pyridine,2,6-luthidine, and the like, and a mixed solvent comprising two or moreof these solvents, if necessary. Above all, xylene, tetrahydrofuran,N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, methanol, pyridine, and the like arepreferred, and N,N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinoneare especially preferred.

The present reaction can be carried out in a wide range of temperaturefrom a temperature of under cooling to under heating, preferably at atemperature of under ice-cooling to the boiling point of the reactionmixture.

(6) The reaction between the compound [9] and the compound [12] to givethe compound [4] can be carried out in the presence of a base in anappropriate solvent, if necessary. The leaving group in the compound[12] can be preferably, for example, a halogen atom.

Examples of the base usable in the present reaction include theinorganic and organic bases. The inorganic bases include alkali metalcarbonates (potassium carbonate, sodium carbonate, and the like), alkalimetal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogencarbonate, and the like), alkali metal hydroxides (sodium hydroxide,potassium hydroxide, lithium hydroxide, and the like), alkali metalhydrides (sodium hydride, and the like). A mixture of cesium carbonateand sodium iodide can also be used. The organic bases include alkalimetal alkoxides (sodium methoxide, potassium t-butoxide, and the like),tri-lower alkylamines (triethylamine, tributylamine,diisopropylethylamine, and the like), tert-amines(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo(5.4.0]-undec-7-ene, and the like), amines(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine, andthe like), pyridine, lutidine and collidine, and the like. Above all,alkali metal carbonates, diisopropylethylamine, pyridine, and the likeare preferred. In the present reaction, the bases above can also be usedas a solvent.

Examples of the solvent usable in the present reaction include any inertsolvent which does not disturb the reaction, such as ketones (e.g.,acetone, methylethyl ketone, and the like), aromatic hydrocarbons(benzene, toluene, xylene, and the like), ethers (diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, andthe like), amides (N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like), nitriles (acetonitrile,and the like), alcohols (methanol, ethanol, propanol, 2-butanol, and thelike), dimethylsulfoxide, pyridine, 2,6-luthidine, and the like. A mixedsolvent comprising two or more of these solvents can also be used. Aboveall, ketones and amides are preferred.

The present reaction can generally be carried out at a temperature ofunder ice-cooling to the reflux temperature of the solvent.

The reaction time for the present reaction is generally between 30minutes and 24 hours; however, longer or shorter reaction time can beselected appropriately, if necessary. Further, an alkali metal iodidesuch as lithium iodide, sodium iodide, potassium iodide, and the likecan also be added, which may facilitate the reaction.

The reaction between the compound [13] and the compound [14] can becarried out in the presence of a base in an appropriate solvent, ifnecessary. The leaving group in the compound [13] can be preferably, forexample, a halogen atom or a nitro group.

Examples of the base usable in the present reaction include alkali metalcarbonates (potassium carbonate, sodium carbonate, cesium carbonate, andthe like), alkali metal hydrides (sodium hydride, and the like) andalkali metal alkoxides (sodium methoxide, potassium t-butoxide, and thelike). Above all, sodium hydride is preferred.

Examples of the solvent usable in the present reaction include amides(N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like) and ethers (diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, andthe like), and N,N-dimethylformamide, N,N-dimethylacetamide,1,3-dimethyl-2-imidazolidinone, and the like are preferred.

The reaction for formylation of the compound [11] to give the compound[10] can be carried out in a conventional manner, if necessary. Forexample, the reaction can be carried out by reacting a formylating agentin accordance with the method for Duff reaction, Gatterman-Kochreaction, Vilsmeier reaction, and the like in an appropriate solvent.

The formylating agent usable in the Duff reaction includes anyconventional ones without limitation, and hexamethylenetetramine, andthe like are preferred.

Examples of the solvent include any inert solvent which does not disturbthe reaction, such as organic acids (acetic acid, propionic acid,trifluoroacetic acid, methanesulfonic acid, and the like), halogenatedhydrocarbons (chloroform, dichloromethane, dichloroethane, and thelike), aromatic hydrocarbons (benzene, toluene, xylene, and the like),ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, and the like), nitrites (acetonitrile, and thelike), water, and a mixed solvent comprising two or more of thesesolvents, if necessary. It is preferred to select any appropriatesolvent depending on the method used.

The present reaction can be carried out in a wide range of temperaturefrom a temperature of under cooling to under heating, preferably at −78°C. to the boiling point of the reaction mixture.

The resulting compounds of the present invention thus produced can beisolated and purified by a procedure well known in the field of organicchemistry such as recrystallization, column chromatography, and thelike.

The present compound [1] or a pharmaceutically acceptable salt thereofhas an excellent inhibitory effect on FXa, and hence is useful in theprevention and treatment of various disorders caused by thrombi andemboli in a mammal (e.g., human, monkey, rabbit, dog, cat, pig, horse,bull, mouse, rat, guinea pig, and the like), which disorders include,for example, stable angina pectoris, unstable angina pectoris, cerebralthrombosis, cerebral infarction, cerebral embolism, transient ischemicattack (TIA), ischemic cerebrovascular disease such as cerebrovascularspasm after subarachnoid hemorrhage, ischemic heart disease caused bycoronary artery thrombogenesis, congestive chronic heart failure,myocardial infarction, acute myocardial infarction, pulmonaryinfarction, pulmonary embolism, pulmonary vascular disorders,economy-class syndrome, kidney disease (diabetic renal disease, chronicglomerulonephritis, IgA nephropathy, and the like), thrombogenesis withatherosclerosis, peripheral arterial occlusion, peripheral venousocclusion, Buerger's disease, deep vein thrombosis, disseminatedintravascular coagulation (DIC), thrombogenesis after implantation of asynthetic vascular prosthesis or replacement of artificial heart valveor joint, intermittent claudication, thrombogenesis and reocclusionafter blood circulation reconstruction such as percutaneous transluminalcoronary angioplasty (PTCA) or percutaneous transluminal coronary arteryrecanalization (PTCR), systemic inflammatory response syndrome (SIRS),multiple organ failure (MODS), thrombogenesis in extracorporealcirculation, blood coagulation in case of blood drawing, diabeticcirculatory disturbance, graft rejection, organ protection andimprovement of function in case of transplantation, and the like

The present compound is characterized in that it shows excellentinhibitory effect on FXa, decreased toxicity, and causes few sideeffects (bleeding, and the like) that are seen in the existinganticoagulants.

When an FXa inhibitor has a small distribution volume (internalmedicine/blood concentration), it would be substantially free of sideeffects such as phospholipidosis, hepatotoxicity, and the like.Accordingly, FXa inhibitors, especially those having the distributionvolume of 0.1-3.0 L/kg and the FXa inhibitory effect with the IC₅₀ valueof 100 nM or below are substantially free of side effects such asphospholipidosis, hepatotoxicity, and the like, and useful as amedicament for treating thrombosis.

The present compound [1] or a pharmaceutically acceptable salt thereofcan be formulated into a pharmaceutical composition comprising atherapeutically effective amount of the compound [1] and apharmaceutically acceptable carrier therefor. The pharmaceuticallyacceptable carriers include diluents, binders (e.g., syrup, gum arabic,gelatine, sorbit, tragacanth, polyvinyl-pyrrolidone), excipients(e.g.,lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine),lubricants (e.g., magnesium stearate, talc, polyethylene glycol,silica), disintegrants (e.g., potato starch) and wetting agents (e.g.,sodium lauryl sulfate), and the like

The compound [1] of the present invention or a pharmaceuticallyacceptable salt thereof can be administered orally or parenterally, andbe used as an appropriate pharmaceutical preparation. Examples of anappropriate preparation for oral administration include solidpreparations (tablets, granules, capsules, powders, and the like),solutions, suspensions and emulsions. Examples of an appropriatepreparation for parenteral administration include suppository,injections or preparation for continuous infusion prepared usingdistilled water for injection, physiological saline or aqueous glucosesolution, and the like, or inhalant.

The dose of the compound [1] or a pharmaceutically acceptable saltthereof of the present invention may vary depending on theadministration routes, and the age, weight and condition of the patient,or the kind or severity of the disease, it is usually in the range ofabout 0.1 to 50 mg/kg/day, preferably about 0.1 to 30 mg/kg/day.

EXAMPLES

The present invention will be illustrated in detail by Examples andReference Examples, but should not be construed to be limited thereto.

Example 1 Methyl2-{[(5-chloropyridin-2-yl)amino]-carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]-cyclohexyl}carbonyl)amino]benzofuran-5-carboxylate

trans-4-[(Dimethylamino)carbonyl]cyclohexanecarboxylic acid (910 mg)obtained in Reference Example 1 is dissolved in thionyl chloride (10ml), and the mixture is stirred at room temperature for 17 hours. Thereaction solution is concentrated under reduced pressure, and theresidue is dissolved in chloroform (6 ml). The mixture is added dropwiseinto a suspension of3-amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide(1.21 g) obtained in Reference Example 78 in pyridine (10 ml) underice-cooling. After the addition, the reaction solution is warmed to roomtemperature, and then stirred for 19 hours. To the reaction solution ispoured a saturated aqueous sodium hydrogen carbonate solution, and themixture is extracted with chloroform. The organic layer is washed withbrine, dried over sodium sulfate, and evaporated to remove the solventunder reduced pressure. The resulting residue is suspended in diethylether and filtered to give the title compound (1.40 g).

APCI-MS M/Z: 527/529[M+H]⁺

Example 2 Methyl[2-{[(5-chloropyridin-2-yl)amino]-carbonyl}-3-({[trans-4-(pyrrolidin-1-ylcarbonyl)-cyclohexyl]carbonyl}amino)benzofuran-5-yl]acetate

trans-4-(Pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylic acid (1.03 g)obtained in Reference Example 2 is dissolved in thionyl chloride (10ml), and the mixture is stirred at room temperature for 17 hours. Thereaction solution is concentrated under reduced pressure, and theresidue is dissolved in chloroform (6 ml). The solution is addeddropwise to a suspension of3-amino-5-methoxycarbonyl-methyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide(1.26 g) obtained in Reference Example 79 in pyridine (10 ml) underice-cooling. After the addition, the reaction solution is warmed to roomtemperature and stirred for 19 hours. To the reaction solution is poureda saturated aqueous sodium hydrogen carbonate solution, and the mixtureis extracted with chloroform. The organic layer is washed with saturatedbrine, dried over sodium sulfate, and evaporated to remove the solventunder reduced pressure. The resulting residue is suspended in diethylether and filtered to give the title compound (1.78 g).

APCI-MS M/Z:567/569[M+H]⁺

Example 3 N²-(5-Chloropyridin-2-yl)-N⁵,N⁵-dimethyl-3-({[trans-4-(morpholin-4-ylcarbonyl)cyclohexyllcarbonyl}-amino)benzofuran-2,5-dicarboxamide

trans-4-(Morpholin-4-ylcarbonyl)cyclohexanecarboxylic acid (109 mg)obtained in Reference Example 3 is dissolved in thionyl chloride (5 ml)and the mixture is stirred at room temperature for 19 hours. Thereaction solution is concentrated under reduced pressure, and theresidue is dissolved in chloroform (4m 1). To the solution is added3-amino-5-dimethylaminocalbonyl-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide(104 mg) obtained in Reference Example 128 under ice-cooling. Afteradding pyridine (4 ml), the reaction solution is warmed to roomtemperature, and stirred for 20 hours. To the reaction solution ispoured a saturated aqueous sodium hydrogen carbonate solution, and themixture is extracted with chloroform. The organic layer is washed withsaturated brine, dried over sodium sulfate, and evaporated to remove thesolvent under reduced pressure. The resulting residue is purified byNH-silica gel column chromatography (eluent: ethyl acetate) to give thetitle compound (81 mg).

APCI-MS M/Z:582/584[M+H]⁺

Example 4N-(5-Chloropyridin-2-yl)-3-[(5-morpholin-4-yl-5-oxopentanoyl)amino]benzofuran-2-carboxamide

5-Morpholin-4-yl-5-oxopentanoic acid (120 mg) obtained in ReferenceExample 6 is dissolved in chloroform (3 ml), and thereto are addedpyridine (97 μl) and thionyl chloride (39 μl) under ice-cooling. Themixture is then stirred at room temperature for 0.5 hours. The resultingreaction solution is cooled with ice, and thereto are added3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (86 mg)obtained in Reference Example 80 and pyridine (2 ml). The reactionsolution is then warmed to room temperature and stirred for 1 hour. Tothe reaction solution is poured a saturated aqueous sodium hydrogencarbonate solution, and the mixture is extracted with chloroform. Theorganic layer is washed with saturated brine, dried over sodium sulfate,and evaporated to remove the solvent under reduced pressure. Theresulting residue is purified by NH-silica gel column chromatography(eluent: chloroform) to give the title compound (125 mg). APCI-MSM/Z:471/473[M+H]⁺

Example 52-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)-amino]benzofuran-5-carboxylicacid

Methyl2-{[(5-chloropyridin-2-yl)amino)carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)-amino]benzofuran-5-carboxylate(1.35 g) obtained in Example 1 is suspended in tetrahydrofuran-methanol(4:1) (20 ml). After adding a solution of sodium hydroxide (205 mg) inwater (5 ml), the mixture is warmed to room temperature and stirred for18 hours. The reaction solution is concentrated under reduced pressure,thereto poured ice-water, and the mixture is acidified by addition of10% hydrochloric acid. The precipitates are collected by filtration,washed with water, and dried to give the title compound (1.23 g).

ESI-MS M/Z:511/513[M−H]⁻

Example 6 N²-(5-Chloropyridin-2-yl)-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-N⁵,N⁵-dimethylbenzofuran-2,5-dicarboxamide

2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylicacid (200 mg) obtained in Example 5 is suspended in chloroform-pyridine(1:3) (8 ml), and thereto are added successively dimethylaminehydrochloride (64 mg), 1-hydroxybenzotriazol (79 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg)under ice-cooling. The mixture is then stirred at room temperature for17 hours. To the reaction solution is poured a saturated aqueous sodiumhydrogen carbonate solution, and the mixture is extracted withchloroform. The organic layer is washed with saturated brine and driedover sodium sulfate. After evaporating the solvent under reducedpressure, the resulting residue is suspended in ethanol-diethyl ether.The precipitates are collected by filtration and dried to give the titlecompound (176 mg).

APCI-MS M/Z:540/542[M+H]⁺

Example 7trans-N′-[2-{[(5-Chloropyridin-2-yl)amino]-carbonyl}-5-(morpholin-4-ylcarbonyl)benzofuran-3-yl]-N,N-dimethylcyclohexane-1,4-dicarboxamide

2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl)cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylicacid (200 mg) obtained in Example 5 is suspended in chloroform-pyridine(1:3) (8 ml) and thereto are added successively morpholine (68 mg),1-hydroxybenzotriazole (79 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg)under ice-cooling. The mixture is then stirred at room temperature for17 hours. To the reaction solution is poured a saturated aqueous sodiumhydrogen carbonate solution, and the mixture is extracted withchloroform. The organic layer is washed with saturated brine and driedover sodium sulfate. After evaporating the solvent under reducedpressure, the resulting residue is suspended in ethanol-diethyl ether.The precipitates are collected by filtration and dried to give the titlecompound (174 mg)

APCI-MS M/Z:582/584[M+H]⁺

Example 8trans-N′-(2-{[(5-Chloropyridin-2-yl)amino)-carbonyl}benzofuran-3-yl)-N,N-dimethylcyclohexane-1,4-dicarboxamide

(1) To thionyl chloride (30 ml) is addedtrans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.79 g) obtained inReference Example 1(2) under ice-cooling, and the mixture is stirred atroom temperature for 17 hours. The reaction solution is concentratedunder reduced pressure and dissolved in chloroform (50 ml), and theretoare added successively3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.88 g)obtained in Reference Example 80 and pyridine (20 ml) under ice-cooling.The reaction solution is warmed to room temperature and stirred for 2hours. To the reaction solution is poured a saturated aqueous sodiumhydrogen carbonate solution, and the mixture is extracted withchloroform. The organic layer is washed successively with water andsaturated brine, dried over sodium sulfate, and evaporated to remove thesolvent under reduced pressure. The resulting residue is suspended indiethyl ether and filtered to give methyltrans-4-{[(2-i[(5-chloropyridin-2-yl)amino]carbonyl}-benzofuran-3-yl)amino]carbonyl}cyclohexanecarboxylate(3.32 g). APCI-MS M/Z:456/458[M+H]⁺

(2) Methyltrans-4-{[(2-{[(5-chloropyridin-2-yl)-amino]carbonyl}benzofuran-3-yl)amino]carbonyl}cyclohexane-carboxylate(300 mg) obtained in Example 8(1) is suspended intetrahydrofuran-methanol (4:1) (10 ml) and thereto is added 10% aqueoussodium hydroxide solution (1 ml). The mixture is warmed to roomtemperature and stirred for 17 hours. The reaction solution isconcentrated under reduced pressure, thereto added ice-water, and themixture is acidified by addition of 10% hydrochloric acid. Theprecipitates are collected by filtration, washed with water, and driedto givetrans-4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}benzofuran-3-yl)amino]carbonyl}-cyclohexanecarboxylicacid (270 mg).

ESI-MS M/Z:440/442[M−H]⁻

(3)trans-4-{[(2-{[(5-Chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]carbonyl}cyclohexane-carboxylicacid (176 mg) obtained in Example 8(2) is suspended in pyridine (8 ml),and thereto are added successively dimethylamine hydrochloride (65 mg),1-hydroxybenzotriazole (108 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg)under ice-cooling, followed by stirring at room temperature for 19hours. To the reaction solution is poured ice-water and the precipitatesare collected by filtration. The resulting precipitates are dissolved inchloroform and dried over sodium sulfate. After evaporating the solventunder reduced pressure, the residue is purified by NH-silica gel columnchromatography (eluent: ethyl acetate) The resulting residue issuspended in n-hexane and the precipitates are collected by filtrationto give the title compound (137 mg). APCI-MS M/Z:469/471[M+H]⁺

Example 95-[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-benzofuran-3-yl)amino]-5-oxopentanoicacid

(1) Monomethyl glutarate (3.32 g) is dissolved in chloroform (50 ml) andthereto are added thionyl chloride (1.75 ml) and N,N-dimethylformamide(one drop). After stirring for 1.5 hours at the same temperature, thereaction solution is cooled, and thereto are added3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (5.00 g)obtained in Reference Example 80 and pyridine (7.0 ml). After stirringfor 2.5 hours at room temperature, the reaction solution is poured into5% hydrochloric acid and extracted with chloroform. The organic layer iswashed successively with saturated brine, a saturated aqueous sodiumhydrogen carbonate solution and saturated brine, dried over sodiumsulfate, and evaporated to remove the solvent under reduced pressure.The resulting residue is suspended in diisopropyl ether and theprecipitates are collected by filtration to give methyl5-[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}benzofuran-3-yl)amino]-5-oxopentanoate(6.16 g). APCI-MS M/Z:416/418[M+H]⁺

(2) Methyl5-[(2-{[(5-chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]-5-oxopentanoate(4.44 g) obtained in Example 9(1) is suspended in methanol (50 ml), andthereto is added 2N aqueous sodium hydroxide solution (30 ml) underice-cooling followed by stirring at room temperature for 2 hours. Afterevaporating methanol under reduced pressure, the residue is diluted withwater and washed with diethyl ether. The separated aqueous layer isacidified with 10% hydrochloric acid under ice-cooling, and theprecipitates are collected by filtration. The resulting solid materialsare washed successively with water, ethanol and diethyl ether, and driedto give the title compound (3.99 g). ESI-MS M/Z:400/402[M−H⁻

Example 106-[(2-{[(5-Chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]-6-oxohexanoicacid

(1) Monomethyl adipate (2.55 g) is dissolved in chloroform (35 ml) andthere to are added thionyl chloride (1.25 ml) and N,N-dimethylformamide(2 drops) at room temperature. The mixture is stirred at the sametemperature for 3 hours and 20 minutes, and thereto are added3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (3.50 g)obtained in Reference Example 80 and pyridine (5.0 ml). After stirringfor 14.5 hours at room temperature, a saturated aqueous sodium hydrogencarbonate solution is added to the reaction solution, and the mixture isextracted with chloroform. The organic layer is washed with saturatedbrine, dried over sodium sulfate, and evaporated to remove the solventunder reduced pressure. The resulting residue is suspended indiisopropyl ether and the precipitates are collected by filtration togive methyl6-[(2-{[(5-chloropyridin-2-yl)aminolcarbonyl}benzofuran-3-yl)amino]-6-oxohexanoate(4.72 g).

APCI-MS M/Z:430/432[M+H]⁺

(2) Methyl6-[(2-{[(5-chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]-6-oxohexanoate(4.30 g) obtained in Example 10(1) is suspended in methanol (5 m), andthereto is added at room temperature 2N aqueous sodium hydroxidesolution (30 ml). The mixture is stirred at room temperature for 4hours, and at 50° C. for 2 hours. The reaction solution is diluted withwater and acidified by addition of 10% hydrochloric acid underice-cooling, and the precipitates are collected by filtration and driedto give the title compound (3.54 g). ESI-MS M/Z:414/416[M−H]⁻

Example 11N-{[(2-{[(5-Chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]carbonyl}-β-alanine

(1) β-Alanine t-butyl ester hydrochloride (3.00 g) is suspended inchloroform (30 ml) and thereto is added triphosgene (1.99 g) underice-cooling, followed by dropwise addition of pyridine (7.0 ml) at thesame temperature over 7 minutes. After stirring at the same temperaturefor 20 minutes, to the reaction solution are added3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (3.07 g)obtained in Reference Example 80 and pyridine (7.0 ml). The mixture isthen heated under reflux for 3 hours and 40 minutes. The reactionsolution is allowed to cool to room temperature, thereto is added 5%hydrochloric acid, and the mixture is extracted with chloroform. Theorganic layer is washed with saturated brine and a saturated aqueoussodium hydrogen carbonate solution, dried over sodium sulfate, andevaporated to remove the solvent under reduced pressure. The resultingresidue is suspended in chloroform-diisopropyl ether and theprecipitates are collected by filtration to giveN-{[(2-([(5-chloropyridin-2-yl)amino]carbonyl}benzofuran-3-yl)amino]carbonyl}-β-alaninet-butyl ester (2.96 g).

APCI-MS M/Z:459/461[M+H]⁺

(2)N-{[(2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-benzofuran-3-yl)amino]carbonyl}-β-alaninet-butyl ester (1.71 g) obtained in Example 11(1) is dissolved intrifluoroacetic acid (15 ml), and the mixture is stirred at roomtemperature for 1 hour and 45 minutes. The reaction solution isconcentrated in vacuo to reduce the volume by about half. To the residueis added diisopropyl ether and the precipitates are collected byfiltration to give the title compound (1.57 g). ESI-MS M/Z:401/403[M−H]⁻

Examples 12-17

The amino compounds and carboxylic acids obtained in Reference Examplesare treated in a similar manner to Example 1, 2, 3 or 4 to give thefollowing compounds. Physicochemical EX. NO. Structure Properties 12

APCI-MS M/Z:533/535 [M + H]⁺ 13

APCI-MS M/Z:541/543 [M + H]⁺ 14

APCI-MS M/Z:527/529 [M + H]⁺ 15

APCI-MS M/Z:553/555 [M + H]⁺ 16

APCI-MS M/Z:485/487 [M + H]⁺ 17

APCI-MS M/Z:470/472 [M + H]⁺

Examples 18-22

The corresponding carboxylic acid esters are treated in a similar mannerto Example 5 to give the following compounds. Physicochemical EX. NO.Structure Properties 18

ESI-MS M/Z:537/539 [M − H]⁻ 19

ESI-MS M/Z:525/527 [M − H]⁻ 20

ESI-MS M/Z:551/553 [M − H]⁻ 21

ESI-MS M/Z:511/513 [M − H]⁻ 22

ESI-MS M/Z:537/539 [M − H]⁻

Examples 23-42

The corresponding carboxylic acids and the corresponding amino compoundsare treated in a similar manner to Example 6 to give the followingcompounds. Physicochemical EX. NO. Structure Properties 23

APCI-MS M/Z:556/558 [M + H]⁺ 24

APCI-MS M/Z:584/586 [M + H]⁺ 25

APCI-MS M/Z:597/599 [M + H]⁺ 26

APCI-MS M/Z:566/568 [M + H]⁺ 27

APCI-MS M/Z:592/594 [M + H]⁺ 28

APCI-MS M/Z:608/610 [M + H]⁺ 29

APCI-MS M/Z:610/612 [M + H]⁺ 30

APCI-MS M/Z:623/625 [M + H]⁺ 31

APCI-MS M/Z:554/556 [M + H]⁺ 32

APCI-MS M/Z:580/582 [M + H]⁺ 33

APCI-MS M/Z:596/598 [M + H]⁺ 34

APCI-MS M/Z:598/600 [M + H]⁺ 35

APCI-MS M/Z:611/613 [M + H]⁺ 36

APCI-MS M/Z:580/582 [M + H]⁺ 37

APCI-MS M/Z:606/608 [M + H]⁺ 38

APCI-MS M/Z:622/624 [M + H]⁺ 39

APCI-MS M/Z:624/626 [M + H]⁺ 40

APCI-MS M/Z:637/639 [M + H]⁺ 41

APCI-MS M/Z:584/586 [M + H]⁺ 42

APCI-MS M/Z:610/612 [M + H]⁺

Example 43N-(5-Chloropyridin-2-yl)-5-(2-hydroxyethyl)-3-({[trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbonyl}-amino)benzofuran-2-carboxamide

Methyl[2-{[(5-chloropyridin-2-yl)aminolcarbonyl}-3-({[trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbonyl}-amino)benzofuran-5-yl)acetate(113 mg) obtained in Example 2 is suspended in tetrahydrofuran-ethanol(6:1) (7 ml). To the suspension is added lithium borohydride (13 mg),and the mixture is stirred at room temperature for 4 hours. Afterpouring 10% hydrochloric acid under ice-cooling, the reaction solutionis stirred at room temperature for several minutes. The reactionsolution is then basified by addition of a saturated aqueous sodiumhydrogen carbonate solution, followed by extraction with chloroform. Theorganic layer is washed with saturated brine, dried over sodium sulfate,and evaporated to remove the solvent under reduced pressure. Theresulting residue is purified by NH-silica gel column chromatography(eluent: chloroform), and the resulting residue is then suspended indiethyl ether. The precipitates are collected by filtration and dried togive the title compound (28 mg). APCI-MS M/Z:539/541[M+H]⁺

Example 44

The corresponding carboxylic acid esters are treated in a similar mannerto Example 43 to give the following compound. Physicochemical EX. NO.Structure Properties 44

APCI-MS M/Z:513/515 [M + H]⁺

Examples 45-92

The carboxylic acids, which are obtained in Example 8(2) and Examples9-11, and corresponding amino compounds are treated in a similar mannerto Example 8(3) to give the following compounds. Physicochemical EX. NO.Structure Properties 45

APCI-MS M/Z:495/497 [M + H]⁺ 46

APCI-MS M/Z:511/513 [M + H]⁺ 47

APCI-MS M/Z:526/528 [M + H]⁺ 48

APCI-MS M/Z:525/527 [M + H]⁺ 49

APCI-MS M/Z:497/499 [M + H]⁺ 50

APCI-MS M/Z:499/501 [M + H]⁺ 51

APCI-MS M/Z:511/513 [M + H]⁺ 52

APCI-MS M/Z:527/529 [M + H]⁺ 53

APCI-MS M/Z:513/515 [M + H]⁺ 54

APCI-MS M/Z:509/511 [M + H]⁺ 55

APCI-MS M/Z:525/527 [M + H]⁺ 56

APCI-MS M/Z:554/556 [M + H]⁺ 57

APCI-MS M/Z:511/513 [M + H]⁺ 58

APCI-MS M/Z:553/555 [M + H]⁺ 59

APCI-MS M/Z:525/527 [M + H]⁺ 60

APCI-MS M/Z:539/541 [M + H]⁺ 61

APCI-MS M/Z:557/559 [M + H]⁺ 62

APCI-MS M/Z:524/526 [M + H]⁺ 63

APCI-MS M/Z:483/485 [M + H]⁺ 64

APCI-MS M/Z:429/431 [M + H]⁺ 65

APCI-MS M/Z:455/457 [M − H]⁺ 66

APCI-MS M/Z:486/488 [M − H]⁺ 67

APCI-MS M/Z:473/475 [M − H]⁺ 68

APCI-MS M/Z:469/471 [M − H]⁺ 69

APCI-MS M/Z:459/461 [M + H]⁺ 70

APCI-MS M/Z:485/487 [M + H]⁺ 71

APCI-MS M/Z:528/530 [M + H]⁺ 72

APCI-MS M/Z:471/473 [M + H]⁺ 73

APCI-MS M/Z:485/487 [M + H]⁺ 74

APCI-MS M/Z:484/486 [M + H]⁺ 75

APCI-MS M/Z:492/494 [M + H]⁺ 76

APCI-MS M/Z:499/501 [M + H]⁺ 77

APCI-MS M/Z:457/459 [M + H]⁺ 78

APCI-MS M/Z:443/445 [M + H]⁺ 79

APCI-MS M/Z:469/471 [M + H]⁺ 80

APCI-MS M/Z:500/502 [M + H]⁺ 81

APCI-MS M/Z:526/528 [M + H]⁺ 82

APCI-MS M/Z:542/544 [M + H]⁺ 83

APCI-MS M/Z:498/500 [M + H]⁺ 84

APCI-MS M/Z:483/485 [M + H]⁺ 85

APCI-MS M/Z:471/473 [M + H]⁺ 86

APCI-MS M/Z:429/431 [M + H]⁺ 87

APCI-MS M/Z:541/543 [M + H]⁺ 88

APCI-MS M/Z:487/489 [M + H]⁺ 89

APCI-MS M/Z:485/487 [M + H]⁺ 90

APCI-MS M/Z:473/475 [M + H]⁺ 91

APCI-MS M/Z:472/474 [M + H]⁺ 92

APCI-MS M/Z:430/432 [M + H]⁺

Examples 93-95

The amino compounds and carboxylic acids obtained in Reference Examplesare treated in a similar manner to Example 1 to give the followingcompounds. Physicochemical EX. NO. Structure Properties 93

APCI-MS M/Z:521 [M + H]⁺ 94

APCI-MS M/Z:528/530 [M + H]⁺ 95

APCI-MS M/Z:521/523 [M + H]⁺

Examples 96-98

The corresponding carboxylic acid esters are tested in a similar mannerto Example 5 to give the following compounds. Physicochemical EX. NO.Structure Properties 96

APCI-MS M/Z:507 [M + H]⁺ 97

ESI-MS M/Z:512/514 [M − H]⁻ 98

ESI-MS M/Z:505/507 [M − H]⁻

Examples 99-123

The corresponding carboxylic acids and the corresponding amino compoundsare treated in a similar manner to Example 6 to give the followingcompounds. Physicochemical EX. NO. Structure Properties 99

APCI-MS M/Z:598/600 [M + H]⁺ 100

APCI-MS M/Z:598/600 [M + H]⁺ 101

APCI-MS M/Z:598/600 [M + H]⁺ 102

APCI-MS M/Z:612/614 [M + H]⁺ 103

APCI-MS M/Z:612/614 [M + H]⁺ 104

APCI-MS M/Z:612/614 [M + H]⁺ 105

APCI-MS M/Z:540/542 [M + H]⁺ 106

APCI-MS M/Z:566/568 [M + H]⁺ 107

APCI-MS M/Z:582/584 [M + H]⁺ 108

APCI-MS M/Z:597/599 [M + H]⁺ 109

APCI-MS M/Z:598/600 [M + H]⁺ 110

APCI-MS M/Z:598/600 [M + H]⁺ 111

APCI-MS M/Z:598/600 [M + H]⁺ 112

APCI-MS M/Z:534 [M + H]⁺ 113

APCI-MS M/Z:560 [M + H]⁺ 114

APCI-MS M/Z:576 [M + H]⁺ 115

APCI-MS M/Z:578 [M + H]⁺ 116

APCI-MS M/Z:591 [M + H]⁺ 117

APCI-MS M/Z:592 [M + H]⁺ 118

APCI-MS M/Z:592 [M + H]⁺ 119

APCI-MS M/Z:592 [M + H]⁺ 120

APCI-MS M/Z:541/543 [M + H]⁺ 121

APCI-MS M/Z:585/587 [M + H]⁺ 122

APCI-MS M/Z:578/580 [M + H]⁺ 123

APCI-MS M/Z:591/593 [M + H]⁺

Examples 124-125

The corresponding amino compounds and carboxylic acids are treated in asimilar manner to Example 1 to give the following compounds.Physicochemical EX. NO. Structure Properties 124

125

Examples 126-127

The corresponding carboxylic acid esters are treated in a similar mannerto Example 5 to give the following compounds. Physicochemical EX. NO.Structure Properties 126

127

Examples 128-143

The corresponding carboxylic acids and the corresponding amino compoundsare treated in a similar manner to Example 6 to give the followingcompounds. Physicochemical EX. NO. Structure Properties 128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

Reference Example 1trans-4-[(Dimethylamino)carbonyl]-cyclohexanecarboxylic acid

(1) Thionyl chloride (254 ml) is added dropwise to methanol (1500 ml)under cooling at −30° C. over a period of about an hour. After theaddition, the reaction mixture is stirred at room temperature for 0.5hours, and thereto is added trans-cyclohexane-1,4-dicarboxylic acid(500.0 g), and the mixture is stirred at room temperature for 17 hours.The reaction solution is concentrated under reduced pressure. Theresidue is diluted with chloroform, and washed with a saturated aqueoussodium hydrogen carbonate solution and saturated brine. The organiclayer is dried over sodium sulfate and evaporated to remove the solventunder reduced pressure. The resulting residue is crystallized fromn-hexane. The product is collected by filtration and dried to givedimethyl trans-cyclohexane-1,4-dicarboxylate (545.0 g). APCI-MSM/Z:201[M+H]⁺

(2) Dimethyl trans-cyclohexane-1,4-dicarboxylate (150.0 g) obtained in(1) above is dissolved in tetrahydrofuran (1500 ml), and to the solutionis added dropwise a mixed solution of 28% sodium methoxide/methanol (149g) and water (13.2 g) under ice-cooling. The reaction solution is warmedto room temperature, stirred for 3.5 hours, and thereto is pouredn-hexane (1500 ml). The mixture is filtered to collect the precipitates.The resulting solid precipitates are added to a mixture of conc.hydrochloric acid (50 ml), water (450 ml) and chloroform (1000 ml) underice-cooling, and the mixture is stirred at room temperature for 20minutes. The chloroform layer is separated and the aqueous layer isextracted with chloroform. The organic layers are combined, dried oversodium sulfate and evaporated to remove the solvent under reducedpressure. The resulting residue is crystallized from n-hexane, collectedby filtration and dried to givetrans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (106.0 g). ESI-MSM/Z:185[M−H]⁻

(3) trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g)obtained in (2) above is dissolved in chloroform (200 ml), and theretoare added dimethylamine hydrochloride (10.5 g),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (24.7 g)and triethylamine (26.0 g) under ice-cooling. The mixture is thenstirred at room temperature for 17 hours. Ice-water is poured to thereaction solution and the mixture is extracted with chloroform. Theorganic layer is washed successively with 10 % hydrochloric acid, asaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over sodium sulfate. The solvent is concentrated underreduced pressure. The resulting residue is purified by silica gel columnchromatography (eluent: chloroform, then chloroform/methanol=20/1) togive methyl trans-4-[(dimethylamino)carbonyl)cyclohexanecarboxylate(20.1 g).

APCI-MS M/Z:214[M+H]⁺

(4) Methyl trans-4-[(dimethylamino)carbonyl]-cyclohexanecarboxylate(20.0 g) obtained in (3) above is dissolved in methanol (100 ml), andthereto is added a solution of sodium hydroxide (7.50 g) in water (40ml). The mixture is then stirred at room temperature for 18 hours. Thereaction solution is concentrated under reduced pressure, and theresidue is diluted with ice-water and washed with diethyl ether. Theresulting aqueous layer is acidified with 10% hydrochloric acid andextracted twice with chloroform. The organic layer is washed withsaturated brine and dried over sodium sulfate. The solvent isconcentrated under reduced pressure. The resulting residue is suspendedin n-hexane and collected by filtration to give the title compound (15.7g).

ESI-MS M/Z:198[M−H]⁻

Reference Example 2trans-4-(Pyrrolidin-1-ylcarbonyl)-cyclohexanecarboxylic acid

(1) trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g)obtained in Reference Example 1(2) is dissolved in chloroform (200 ml),and thereto are added pyrrolidine (9.2 g),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (24.7 g)and triethylamine (13.6 g) under ice-cooling. The mixture is thenstirred at room temperature for 17 hours. Ice-water is poured to thereaction solution and the mixture is extracted with chloroform. Theorganic layer is washed successively with 10% hydrochloric acid, asaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over sodium sulfate. The solvent is concentrated underreduced pressure. The resulting residue is purified by silica gel columnchromatography (eluent: chloroform, then chloroform/methanol=20/1) togive methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate(11.8 g).

APCI-MS M/Z:240[M+H]⁺

(2) Methyl trans-4-(pyrrolidin-1-ylcarbonyl)-cyclohexanecarboxylate(11.7 g) obtained in (1) above is dissolved in methanol (50 ml), andthereto is added a solution of sodium hydroxide (3.95 g) in water (20ml). The mixture is then stirred at room temperature for 18 hours. Thereaction solution is concentrated under reduced pressure. The residue isdiluted with ice-water and washed with diethyl ether. The resultingaqueous layer is acidified with 10% hydrochloric acid and extractedtwice with chloroform. The organic layer is washed with saturated brineand dried over sodium sulfate. The solvent is concentrated under reducedpressure. The resulting residue is suspended in n-hexane and collectedby filtration to give the title compound (10.1 g).

ESI-MS M/Z:224[M−H]⁻

Reference Example 3trans-4-(Morpholin-4-ylcarbonyl)-cyclohexanecarboxylic acid

(1) trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (800 mg)obtained in Reference Example 1(2) is dissolved in chloroform (30 ml),and thereto are added morpholine (560 mg),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.24 g)and triethylamine (650 mg) under ice-cooling. The mixture is thenstirred at room temperature for 19 hours. Ice-water is poured to thereaction solution and the mixture is extracted with chloroform. Theorganic layer is washed successively with 10% hydrochloric acid, asaturated aqueous sodium hydrogen carbonate solution and saturated brineand dried over sodium sulfate. The solvent is concentrated under reducedpressure. The resulting residue is purified by silica gel columnchromatography (eluent: chloroform, then chloroform/methanol=30/1) togive methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexanecarboxylate (897mg).

APCI-MS M/Z:256[M+H]⁺

(2) Methyl trans-4-(morpholin-4-ylcarbonyl)-cyclohexanecarboxylate (860mg) obtained in (1) above is dissolved in methanol (40 ml), and theretois added 4 N aqueous sodium hydroxide solution (1.68 ml). The mixture isthen stirred at room temperature for 18 hours. The reaction solution isconcentrated under reduced pressure. The residue is diluted withice-water, neutralized with 10% hydrochloric acid, and extracted withchloroform. The organic layer is dried over sodium sulfate and thesolvent is concentrated under reduced pressure to give the titlecompound (638 mg). ESI-MS M/Z:240[M−H]⁻

Reference Example 4trans-4-{[[2-(Dimethylamino)ethyl]-(methyl)amino]carbonyl}cyclohexanecarboxylicacid

(1) trans-4- (Methoxycarbonyl)cyclohexanecarboxylic acid (8.84 g)obtained in Reference Example 1(2) is dissolved in chloroform (100 ml),and thereto are added 1-hydroxybenzotriazole (7.14 g),1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (10.00 g)and N,N,N′-trimethylethylenediamine (5.33 g) under ice-cooling. Themixture is then stirred at room temperature for 4 hours. Saturatedaqueous sodium hydrogen carbonate solution is poured to the reactionsolution and the mixture is extracted with chloroform. The organic layeris washed with saturated brine and dried over sodium sulfate. Thesolvent is concentrated under reduced pressure. The resulting residue ispurified by silica gel column chromatography (eluent:chloroform/methanol/28% ammonia water=200/10/1) to give methyltrans-4-{[[2-(dimethylamino)ethyl)(methyl)amino]carbonyl}-cyclohexanecarboxylate(11.98 g). APCI-MS M/Z:271[M+H]⁺

(2) Methyltrans-4-{[[2-(dimethylamino)ethyl](methyl)-amino]carbonyl}cyclohexanecarboxylate(6.32 g) obtained in (1) above is dissolved in methanol (20 ml), andthereto is added 1 N aqueous sodium hydroxide solution (25 ml). Themixture is stirred at room temperature for 3 hours. To the reactionsolution is added 1 N hydrochloric acid (25 ml) and the reactionsolution is concentrated under reduced pressure. The residue islyophilized to give the crude title compound which contains equimolarsodium chloride (6.71 g). APCI-MS M/Z:257[M+H]⁺

Reference Example 5 6-Morpholin-4-yl-6-oxohexanoic acid

(1) Monomethyl adipate (3.20 g) is dissolved in chloroform (70 ml), andthereto are added morpholine (2.61 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.75 g) andtriethylamine (3.04 g) under ice-cooling. The mixture is then stirred atroom temperature for 19 hours. Ice-water is added to the reactionsolution and the mixture is extracted with chloroform. The organic layeris washed successively with 10% hydrochloric acid, a saturated aqueoussodium hydrogen carbonate solution and saturated brine, and dried oversodium sulfate. The solvent is removed by evaporation under reducedpressure to give methyl 6-morpholin-4-yl-6-oxohexanoate (4.63 g).APCI-MS M/Z:230[M+H]⁺

(2) Methyl 6-morpholin-4-yl-6-oxohexanoate (4.60 g) obtained in (1)above is dissolved in methanol (20 ml), and thereto is added a solutionof sodium hydroxide (1.61 g) in water (8 ml). The mixture is stirred atroom temperature for 19 hours. The reaction solution is concentratedunder reduced pressure and the residue is neutralized with 2 Nhydrochloric acid. The residue is concentrated under reduced pressureand extracted with chloroform. The organic layer is dried over sodiumsulfate and the solvent is concentrated under reduced pressure to givethe title compound (4.11 g). ESI-MS M/Z:214[M−H]⁻

Reference Example 6 5-Morpholin-4-yl-5-oxopentanoic acid

anhydride (1.14 g) is dissolved in tetrahydrofuran (20 ml), and theretois added morpholine (0.87 g). The mixture is then stirred at roomtemperature for 19 hours. The reaction solution is concentrated underreduced pressure, and the residue is diluted with chloroform and washedwith 10% hydrochloric acid. The organic layer is dried over sodiumsulfate and evaporated to remove the solvent under reduced pressure togive the title compound (1.05 g). ESI-MS M/Z:200[M−H]⁻

Reference Example 7 Methyl 3-formyl-4-hydroxybenzoate

Methyl 4-hydroxybenzoate (1.52 g) is dissolved in trifluoroacetic acid(20 ml), and thereto is added hexamethylenetetramine (700 mg). Themixture is heated under reflux for 2 hours. The reaction solution isconcentrated under reduced pressure, and thereto is poured ice-water.The mixture is then extracted with ethyl acetate. The organic layer iswashed with a saturated aqueous sodium hydrogen carbonate solution andsaturated brine, dried over sodium sulfate and evaporated to remove thesolvent under reduced pressure. The resulting residue is dissolved inchloroform, and filtered to remove the insoluble materials. The filtrateis concentrated under reduced pressure, and purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=4/1) to give thetitle compound (540 mg). ESI-MS M/Z:179[M−H]⁻

Reference Example 8 Methyl (3-formyl-4-hydroxyphenyl)-acetate

Methyl (4-hydroxyphenyl)acetate (1.66 g) is dissolved in trifluoroaceticacid (20 ml), thereto is added hexamethylenetetramine (700 mg), and themixture is heated under reflux for 2 hours. The reaction solution isconcentrated under reduced pressure, thereto is poured ice-water, andthen the mixture is extracted with ethyl acetate. The organic layer iswashed with a saturated aqueous sodium hydrogen carbonate solution andsaturated brine, dried over sodium sulfate, and evaporated to remove thesolvent under reduced pressure. The resulting residue is purified bysilica gel column chromatography (eluent: n-hexane/ethyl acetate =9/1,then 4/1) to give the title compound (1.08 g). ESI-MS M/Z:193[M−H]⁻

Reference Examples 9-10

The corresponding starting compounds are treated in a similar manner toReference Example 7 or Reference Example 8 to give the followingcompounds. Ref. Physicochemical Ex. No. Structure Properties 9

APCI-MS M/Z:225 [M + H + MeOH − H₂O]⁺ 10

EI-MS M/Z:265 [M]⁺

Reference Example 11 Methyl 3-cyano-4-hydroxybenzoate

Methyl 3-formyl-4-hydroxybenzoate (28.60 g) obtained in ReferenceExample 7 is dissolved in formic acid (120 ml), thereto is addedhydroxylammonium chloride (14.30 g), and the mixture is heated underreflux for 15 hours. The reaction solution is concentrated under reducedpressure, diluted with ethyl acetate, washed successively with water andsaturated brine, dried over sodium sulfate and evaporated to remove thesolvent under reduced pressure to give the title compound (24.25 g).ESI-MS M/Z:176[M−H]⁻

Reference Example 12 Methyl (3-cyano-4-hydroxyphenyl)-acetate

Methyl (3-formyl-4-hydroxyphenyl)acetate (1.05 g) obtained in ReferenceExample 8 is dissolved in formic acid (15 ml), and thereto are addedhydroxylammonium chloride (0.49 g) and sodium formate (0.81 g), and themixture is heated under reflux for 8 hours. The reaction solution isconcentrated under reduced pressure, diluted with ethyl acetate, washedsuccessively with water and saturated brine, dried over sodium sulfate,and evaporated to remove the solvent under reduced pressure to give thetitle compound (520 mg). ESI-MS M/Z:190[M−H]⁻

Reference Examples 13-25

The corresponding starting compounds are treated in a similar manner toReference Example 11 or 12 to give the following compounds. Physico-Ref. chemical Ex. No. Structure Properties 13

ESI-MS M/Z:192 [M − H]⁻ 14

APCI-MS M/Z:263 [M + H]⁺ 15

ESI-MS M/Z:152/154 [M − H]⁻ 16

ESI-MS M/Z:196/198 [M − H]⁻ 17

ESI-MS M/Z:132 [M − H]⁻ 18

ESI-MS M/Z:163 [M − H]⁻ 19

ESI-MS M/Z:148 [M − H]⁻ 20

ESI-MS M/Z:148 [M − H]⁻ 21

ESI-MS M/Z:196/198 [M − H]⁻ 22

ESI-MS M/Z:132 [M − H]⁻ 23

This compound is used in the next step without further purification. 24

ESI-MS M/Z:148 [M − H]⁻ 25

This compound is used in the next step without further purification.

Reference Example 262-(4-Methoxycarbonyl-2-cyano-phenoxy)-N-(5-chloropyridin-2-yl)acetamide

(1) Chloroacetyl chloride (95.5 ml) is dissolved in dichloromethane (500ml), and thereto is added dropwise a suspension of2-amino-5-chloropyridine (128.6 g) and triethylamine (169 ml) indichloromethane (1000 ml) under ice-cooling. The reaction solution iswarmed to room temperature and stirred for 0.5 hours. The reactionsolution is concentrated under reduced pressure, and thereto is pouredice-water. The reaction mixture is extracted with ethyl acetate. Theorganic layer is washed with saturated brine, dried over sodium sulfateand treated with activated charcoal. Insoluble materials are removed byfiltration and the filtrate is concentrated under reduced pressure. Theresulting residue is suspended in diisopropyl ether. The precipitatesare collected by filtration, washed with diisopropyl ether and dried togive 2-chloro-N-(5-chloropyridin-2-yl)acetamide (153.4 g).

APCI-MS M/Z:205/207[M+H]⁺

(2) Methyl 3-cyano-4-hydroxybenzoate (500 mg) obtained in ReferenceExample 11 is dissolved in acetone (25 ml), and thereto are added2-chloro-N-(5-chloropyridin-2-yl)acetamide (695 mg) obtained in (1)above, potassium carbonate (546 mg) and sodium iodide (550 mg). Themixture is heated under reflux for 2 hours. After allowing to cool,insoluble materials are removed by filtration and the insolubles arewashed with acetone several times. The filtrate and washings arecombined, concentrated under reduced pressure, and purified by silicagel column chromatography (eluent: chloroform, then chloroform/ethylacetate=4/1). The resulting residue is suspended in diethyl ether, andthe precipitates are collected by filtration to give the title compound(660 mg).

APCI-MS M/Z:346/348[M+H]⁺

Reference Example 272-[2-Cyano-4-(methoxycarbonyl-methyl)phenoxy]-N-(5-chloropyridin-2-yl)acetamide

Methyl (3-cyano-4-hydroxyphenyl)acetate (500 mg) obtained in ReferenceExample 12 is dissolved in acetone (25 ml), and thereto are added2-chloro-N-(5-chloropyridin-2-yl)acetamide (640 mg) obtained inReference Example 26(1), cesium carbonate (1.20 g) and sodium iodide(510 mg). The mixture is heated under reflux for 5 hours. After allowingto cool, the insoluble materials are removed by filtration and theinsolubles are washed with acetone several times. The filtrate and thewashings are combined and concentrated under reduced pressure. To theresidue is poured water, and the mixture is extracted with ethylacetate. The organic layer is washed with saturated brine, dried oversodium sulfate and evaporated to remove the solvent under reducedpressure. The resulting residue is purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate/chloroform=3/1/1) Theresulting residue is suspended in diethyl ether-n-hexane, and theprecipitates are collected by filtration to give the title compound (570mg). APCI-MS M/Z:360/362[M+H]⁺

Reference Example 28-29

The corresponding starting compounds are treated in a similar manner toReference Example 26 or 27 to give the following compounds. Ref.Physicochemical Ex. No. Structure Properties 28

APCI-MS M/Z:376/378 [M + H]⁺ 29

APCI-MS M/Z:431/433 [M + H]⁺

Reference Example 30 t-Butyl (2-cyanophenoxy)acetate

2-Cyanophenol (107.1 g) is dissolved in acetone (1000 ml) and thereto isadded t-butyl bromoacetate (200.0 g). Potassium carbonate (141.6 g) isadded, and the reaction solution is heated under reflux for 2 hours.After allowing to cool, the insoluble materials are removed byfiltration, and the insolubles are washed with acetone several times.The filtrate and washings are combined, concentrated under reducedpressure and treated with diisopropyl ether azeotropically. Theresulting residue is crystallized from n-hexane-diisopropyl ether (5/1)(600 ml), followed by stirring under ice-cooling. The precipitates arecollected by filtration, washed with cold n-hexane-diisopropyl ether(10/1) (600 ml) several times, and dried to give the title compound(194.5 g).

APCI-MS M/Z:251[M+NH₄]⁺

Reference Examples 31-42

The corresponding starting compounds are treated in a similar manner toReference Example 30 to give the following compounds. Ref.Physicochemical Ex. No. Structure Properties 31

APCI-MS M/Z:309 [M + NH₄]⁺ 32

APCI-MS M/Z:285/287 [M + NH₄]⁺ 33

APCI-MS M/Z:329/331 [M + NH₄]⁺ 34

APCI-MS M/Z:265 [M + NH₄]⁺ 35

APCI-MS M/Z:296 [M + NH₄]⁺ 36

APCI-MS M/Z:281 [M + NH₄]⁺ 37

APCI-MS M/Z:281 [M + NH₄]⁺ 38

APCI-MS M/Z:329/331 [M + NH₄]⁺ 39

APCI-MS M/Z:265 [M + NH₄]⁺ 40

APCI-MS M/Z:305 [M + H]⁺ 41

APCI-MS M/Z:281 [M + NH₄]⁺ 42

APCI-MS M/Z:265 [M + NH₄]⁺

Reference Example 43 (2-Cyanophenoxy)acetic acid

t-Butyl (2-cyanophenoxy)acetate (300.0 g) obtained in Reference Example30 is dissolved in dichloromethane (400 ml), and thereto is addedtrifluoroacetic acid (990 ml) and the mixture is stirred at roomtemperature for 4 hours. The reaction solution is concentrated underreduced pressure, and the resulting residue is suspended in diethylether (100 ml). To the suspension is poured diisopropyl ether (500 ml).The precipitates are collected by filtration, washed with diisopropylether several times and dried to give the title compound (198.4 g).

ESI-MS M/Z:176[M−H]⁻

Reference Examples 44-55

The corresponding starting compounds are treated in a similar manner toReference Example 43 to give the following compounds. Ref.Physicochemical Ex. No. Structure Properties 44

ESI-MS M/Z:234 [M − H]⁻ 45

ESI-MS M/Z:210/212 [M − H]⁻ 46

ESI-MS M/Z:254/256 [M − H]⁻ 47

ESI-MS M/Z:190 [M − H]⁻ 48

ESI-MS M/Z:221 [M − H]⁻ 49

ESI-MS M/Z:206 [M − H]⁻ 50

ESI-MS M/Z:206 [M − H]⁻ 51

ESI-MS M/Z:254/256 [M − H]⁻ 52

ESI-MS M/Z:190 [M − H]⁻ 53

ESI-MS M/Z:247 [M − H]⁻ 54

ESI-MS M/Z:206 [M − H]⁻ 55

ESI-MS M/Z:190 [M − H]⁻

Reference Example 56 [4-(N-Benzyloxycarbonyl-N-methyl-amino)-2-cyanophenoxy]acetic acid

(1) t-Butyl 2-(4-nitro-2-cyanophenoxy)acetate (500 mg) obtained inReference Example 35 is dissolved in tetrahydrofuran (20 ml), andthereto is added 10% palladium-carbon (100 mg) The mixture is stirredfor 2 hours under atmospheric hydrogen pressure. The insoluble materialsare removed by filtration, and the filtrate is concentrated underreduced pressure to give t-butyl (4-amino-2-cyanophenoxy) acetate (440mg).

APCI-MS M/Z:249[M+H]⁺

(2) t-Butyl (4-amino-2-cyanophenoxy)acetate (430 mg) obtained in (1)above is dissolved in tetrahydrofuran (10 ml), and thereto is added asaturated sodium hydrogen carbonate solution (10 ml). Benzylchloroformate (355 mg) is further added under ice-cooling. Underice-cooling, the reaction solution is stirred for 1 hour and extractedwith ethyl acetate. The organic layer is washed with saturated brine,dried over sodium sulfate, and evaporated to remove the solvent underreduced pressure. The resulting residue is purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=9/1, then 3/1) to givet-butyl (4-benzyloxycarbonylamino-2-cyanophenoxy) acetate (540 mg).

APCI-MS M/Z:383[M+H]⁺

(3) t-Butyl (4-benzyloxycarbonylamino-2-cyanophenoxy)acetate (100 mg)obtained in (2) above is dissolved in N,N-dimethylformamide (3 ml) andthereto is added 60% oleaginous sodium hydride (12.5 mg). After stirringfor 20 minutes at room temperature, methyl iodide (24.4 μl) is addeddropwise and the mixture is further stirred for one hour. To thereaction solution is poured a saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic layer is washedsuccessively with water and saturated brine, dried over sodium sulfateand evaporated to remove the solvent. The resulting residue is purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1,then 3/1) to give t-butyl[4-(N-benzyloxycarbonyl-N-methylamino)-2-cyanophenoxy]acetate (91 mg).APCI-MS M/Z:414[M+NH₄]⁺

(4) t-Butyl[4-(N-benzyloxycarbonyl-N-methylamino)-2-cyanophenoxy]acetate (2.42 g)obtained in (3) above is treated in a similar manner to ReferenceExample 43 to give the title compound (2.06 g). ESI-MS M/Z:339[M−H]⁻

Reference Example 57 (2-Cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide

(2-Cyanophenoxy)acetic acid (48.63 g) obtained in Reference Example 43is dissolved in dichloromethane (1000 ml), thereto are added oxalylchloride (26.34 ml) and N,N-dimethylformamide (10 drops), and themixture is stirred at room temperature for 3.5 hours. The reactionsolution is cooled on ice-bath, and thereto is added2-amino-5-chloropyridine (32.08 g), followed by addition of pyridine(60.54 ml). After 5 minutes, the reaction solution is warmed to roomtemperature and stirred overnight. After adding ice-water, the solutionis adjusted to about pH 4 with 10% hydrochloric acid, and extracted withchloroform. The organic layer is washed successively with water, asaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over sodium sulfate and evaporated to remove the solvent.The resulting residue is suspended in chloroform-ethyl acetate andcollected by filtration to give(2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (51.58 g). Thefiltrate is concentrated under reduced pressure, and purified by silicagel column chromatography (eluent: chloroform) to give the titlecompound (11.50 g).

APCI-MS M/Z:288/290[M+H]⁺

Reference Examples 58-72

The corresponding starting compounds are treated in a similar manner toReference Example 57 to give the following compounds. Ref.Physicochemical Ex. No. Structure Properties 58

APCI-MS M/Z:332/334 [M + H]⁺ 59

APCI-MS M/Z:268 [M + H]⁺ 60

APCI-MS M/Z:326 [M + H]⁺ 61

APCI-MS M/Z:332/334 [M + H]⁺ 62

APCI-MS M/Z:366/368 [M + H]⁺ 63

APCI-MS M/Z:302/304 [M + H]⁺ 64

APCI-MS M/Z:329/331 [M + H]⁺ 65

APCI-MS M/Z:318/320 [M + H]⁺ 66

APCI-MS M/Z:451/453 [M + H]⁺ 67

APCI-MS M/Z:318/320 [M + H]⁺ 68

APCI-MS M/Z:366/368 [M + H]⁺ 69

APCI-MS M/Z:302/304 [M + H]⁺ 70

APCI-MS M/Z:359/361 [M + H]⁺ 71

APCI-MS M/Z:318/320 [M + H]⁺ 72

APCI-MS M/Z:302/304 [M + H]⁺

Reference Example 73 (2-Cyanophenoxy)-N-(4-chlorophenyl)-acetamide

(2-Cyanophenoxy)acetic acid (30.00 g) obtained in Reference Example 43is dissolved in N,N-dimethylformamide (300 ml), thereto are addedsuccessively 4-chloroaniline (25.9 g), 4-dimethylaminopyridine (22.7 g)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.6g), and the mixture is stirred at room temperature for 3 hours. Thereaction solution is concentrated under reduced pressure. The resultingresidue is diluted with ethyl acetate-tetrahydrofuran, washedsuccessively with water, 5% hydrochloric acid, water and saturatedbrine, dried over sodium sulfate and evaporated to remove the solvent.The resulting residue is suspended in diisopropyl ether, and theprecipitates are collected by filtration to give the title compound(44.00 g). APCI-MS M/Z:287/289[M+H]⁺

Reference Examples 74-77

The corresponding starting compounds are treated in a similar manner toReference Example 73 to give the following compounds. Ref.Physicochemical Ex. No. Structure Properties 74

APCI-MS M/Z:331/333 [M + H]⁺ 75

APCI-MS M/Z:267 [M + H]⁺ 76

APCI-MS M/Z:271 [M + H]⁺ 77

APCI-MS M/Z:283 [M + H]⁺

Reference Example 783-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-(4-Methoxycarbonyl-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide(1.73 g) obtained in Reference Example 26 is dissolved inN,N-dimethylacetamide (15 ml), thereto is added sodium carbonate (160mg), and the mixture is stirred at 100° C. for 2 hours. After allowingto cool, to the reaction solution is poured ice-water. The resultingprecipitates are collected by filtration, washed successively withwater, tetrahydrofuran and diethyl ether and dried to give the titlecompound (1.20 g).

APCI-MS M/Z:346/348[M+H]⁺

Reference Example 793-Amino-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-[2-Cyano-4-(methoxycarbonylmethyl)phenoxy]-N-(5-chloropyridin-2-yl)acetamide(500 mg) obtained in Reference Example 27 is dissolved inN,N-dimethylacetamide (15 ml), thereto is added sodium carbonate (74mg), and the mixture is stirred at 100° C. for 16 hours. After allowingto cool, to the reaction solution is poured ice-water and extracted withethyl acetate. The organic layer is washed successively with water andsaturated brine, dried over sodium sulfate and evaporated to remove thesolvent. The resulting residue is purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate/chloroform=3/1/1),suspended in diethyl ether-n-hexane, and then the precipitates arecollected by filtration to give title compound (180 mg). APCI-MSM/Z:360/362[M+H]⁺

Reference Example 803-Amino-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide

(2-Cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (150.00 g) obtainedin Reference Example 57 is dissolved in N,N-dimethylacetamide (1500 ml),thereto is added sodium carbonate (60.8 g) and the mixture is stirred at70° C. for 7 hours. After allowing to cool, the reaction solution ispoured to ice-water. The resulting precipitates are collected byfiltration and washed with water several times. The precipitates aredissolved in ethyl acetate, washed with water and saturated brine, anddried over sodium sulfate. The organic layer is treated with activatedcharcoal. The insoluble materials are filtered, and the filtrate isconcentrated under reduced pressure. The resulting residue is suspendedin diethyl ether-ethyl acetate. The precipitates are collected byfiltration, washed with diethyl ether, and dried to give the titlecompound (119.33 g). APCI-MS M/Z: 288/290[M+H]⁺

Reference Examples 81-102

The corresponding starting compounds are treated in a similar manner toReference Example 78, 79 or 80 to give the following compounds. Ref.Physicochemical Ex. No. Structure Properties  81

APCI-MS M/Z: 332/334 [M + H]⁺  82

APCI-MS M/Z: 268 [M + H]⁺  83

APCI-MS M/Z: 287/289 [M + H]⁺  84

APCI-MS M/Z: 331/333 [M + H]⁺  85

APCI-MS M/Z: 267 [M + H]⁺  86

APCI-MS M/Z: 271 [M + H]⁺  87

APCI-MS M/Z: 283 [M + H]⁺  88

APCI-MS M/Z: 326 [M + H]⁺  89

APCI-MS M/Z: 322/324 [M + H]⁺  90

APCI-MS M/Z: 366/368 [M + H]⁺  91

APCI-MS M/Z: 302/304 [M + H]⁺  92

APCI-MS M/Z: 333/335 [M + H]⁺  93

APCI-MS M/Z: 318/320 [M + H]⁺  94

APCI-MS M/Z: 376/378 [M + H]⁺  95

APCI-MS M/Z: 431/433 [M + H]⁺  96

APCI-MS M/Z: 451/453 [M + H]⁺  97

APCI-MS M/Z: 318/320 [M + H]⁺  98

APCI-MS M/Z: 366/368 [M + H]⁺  99

APCI-MS M/Z: 302/304 [M + H]⁺ 100

APCI-MS M/Z: 359/361 [M + H]⁺ 101

APCI-MS M/Z: 318/320 [M + H]⁺ 102

APCI-MS M/Z: 302/304 [M + H]⁺

Reference Example 103(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide

To a suspension of(2-cyano-4-methoxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (40.0 g)obtained in Reference Example 65 in dichloromethane (2000 ml) is addeddropwise boron tribromide (173 g) at −58° C. over 40 minutes. Thereaction solution is stirred for 26 hours while keeping the internaltemperature between −20° C. and 0° C., and then poured to ice-water. Theprecipitated solids are collected by filtration, washed with water, anddried under reduced pressure. A portion (24.3 g) of the resulting solids(37.2 g) are purified by silica gel column chromatography (eluent:chloroform/methanol=50/1-10/1) to give the title compound (17.0 g).APCI-MS M/Z:304/306[M+H]⁺

Reference Example 1043-Amino-5-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (321 mg)obtained in Reference Example 103 is treated in a similar manner toReference Example 79 to give the title compound (274 mg). APCI-MSM/Z:304/306[M+H]⁺

Reference Example 105(4-t-Buthoxycarbonylmethoxy-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide

(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (5.75 g)obtained in Reference Example 103 is dissolved in acetone (160 ml), andthereto are added cesium carbonate (8.08 g), t-butyl bromoacetate (4.58g) and sodium iodide (3.64 g). After the reaction solution is heatedunder reflux for 8 hours, cesium carbonate (1.89 g), t-butylbromoacetate (840 μl) and sodium iodide (875 mg) are further added, andthe mixture is heated under reflux for additional 14 hours. The reactionsolution is allowed to cool, poured to an ice-water, adjusted the pH to1-2 with 10% hydrochloric acid, and then extracted with ethyl acetate.The organic layer is dried over sodium sulfate and evaporated to removethe solvent. The resulting residue is purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1, 2/1, and then 1/1) andthereafter by NH-silica gel column chromatography (eluent: hexane/ethylacetate=2/1, then 1/1) to give the title compound (4.02 g). APCI-MSM/Z:418/420[M+H]⁺

Reference Example 1063-Amino-5-t-butoxycarbonylmethoxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(4-t-Buthoxycarbonylmethoxy-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide(8.18 g) obtained in Reference Example 105 is treated in a similarmanner to Reference Example 79 to give the title compound (5.72 g).

APCI-MS M/Z:418/420[M+H]⁺

Reference Example 1073-Amino-5-(2-methoxyethoxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(1) (2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (100mg) obtained in Reference Example 103 is dissolved in tetrahydrofuran,and thereto are added 2-methoxyethanol (9.30 ml) and triphenylphosphine(31.0 g) To the mixture is further added dropwise diethylazodicarboxylate (22.2 ml) under ice-cooling. The reaction solution iswarmed to room temperature, stirred for 17 hours and concentrated underreduced pressure. To the resulting residue is poured diisopropyl ether,and the insoluble materials are removed by filtration. The filtrate isconcentrated under reduced pressure. The resulting residue is purifiedby silica gel column chromatography (eluent: chloroform/ethylacetate=10/1) to give, as a crude material,[4-(2-methoxyethoxy)-2-cyanophenoxy]-N-(5-chloropyridin-2-yl)acetamide(71.48 g), which is used in the next step without further purification.

APCI-MS M/Z:362/364[M+H]⁺

(2) The -crude material (71.48 g) containing[4-(2-methoxyethoxy)-2-cyanophenoxy]-N-(5-chloropyridin-2-yl)acetamideobtained in (1) above is treated in a similar manner to ReferenceExample 78 to give the title compound (24.40 g). APCI-MSM/Z:362/364[M+H]⁺

Reference Examples 108-112

(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide obtained inReference Example 103 and a corresponding alcohol are treated in asimilar manner to Reference Example 101 to give the following compounds.Ref. Physicochemical Ex. No. Structure Properties 108

APCI-MS M/Z: 375/377 [M + H]⁺ 109

APCI-MS M/Z: 406/408 [M + H]⁺ 110

APCI-MS M/Z: 466/468 [M + H]⁺ 111

APCI-MS M/Z: 461/463 [M + H]⁺ 112

APCI-MS M/Z: 463/465 [M + H]⁺

Reference Example 113(2,4-Dicyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide

4-Nitrobenzonitrile (3.02 g) and potassium cyanide (2.02 g) aredissolved in dimethyl sulfoxide (100 ml), and the solution is stirred at100° C. for an hour. The reaction solution is allowed to cool to roomtemperature, and thereto are added potassium carbonate (1.49 g),2-chloro-N-(5-chloropyridin-2-yl)acetamide (10.42 g) obtained inReference Example 26(1) and sodium iodide (8.76 g), and the mixture isstirred at 60° C. for 4.5 hours. The reaction solution is poured towater, and the precipitated solids are collected by filtration, washedwith water and air-dried. The resulting solids are dissolved in ethylacetate, and the solution is dried over sodium sulfate and evaporated toremove the solvent under reduced pressure. The resulting residue ispurified by silica gel column chromatography (eluent: hexane/ethylacetate=5/1 to 1/1), and the resulting residue is then suspended inethyl acetate-diisopropyl ether. The precipitates are collected byfiltration and dried to give the title compound (2.81 g).

APCI-MS M/Z:313/315[M+H]⁺

Reference Example 1143-Amino-5-cyano-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(2,4-Dicyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (1.02 g) obtainedin Reference Example 113 is treated in a similar manner to ReferenceExample 79 to give the title compound (0.96 g). APCI-MSM/Z:313/315[M+H]⁺

Reference Example 115(3-Chloro-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide

(1) 2-Chloro-N- (5-chloropyridin-2-yl)acetamide (30.68 g) obtained inReference Example 26(1) is dissolved in N,N-dimethylformamide (500 ml),thereto is added sodium acetate (24.55 g), and the mixture is stirred at60° C. for 5 hours. The reaction solution is diluted with ethyl acetate,washed successively with water and saturated brine. The solution isdried over magnesium sulfate, treated with activated charcoal, and thefiltrate is concentrated under reduced pressure. The resulting residueis suspended in n-hexane and crystals are collected by filtration,washed with n-hexane, and dried to giveN-(5-chloropyridin-2-yl)-2-acetoxyacetamide (30.58 g). APCI-MSM/Z:229/231[M+H]⁺

(2) 2-Acetoxy-N-(5-chloropyridin-2-yl)acetamide (30.36 g) obtained in(l) above is suspended in methanol (1200 ml), and thereto is addedpotassium carbonate (22.0 g) under ice-cooling. The reaction solution iswarmed to room temperature, stirred for 0.5 hours, and concentratedunder reduced pressure. Ethyl acetate (1500 ml) and ice-water (1000 ml)are poured to the resulting residue, and the mixture is extracted withethyl acetate. The organic layer is washed with saturated brine, driedover sodium sulfate, and evaporated to remove the solvent under reducedpressure. The resulting residue is suspended in a small amount of ethylacetate, and thereto is added diisopropyl ether. The precipitatedcrystals are collected by filtration, washed with diisopropyl ether anddried to give 2-hydroxy-N-(5-chloropyridin-2-yl)acetamide (22.85 g).

APCI-MS M/Z:187/189[M+H]⁺

(3) 2-Chloro-6-nitrobenzonitrile (187 mg) and2-hydroxy-N-(5-chloropyridin-2-yl)acetamide (183 mg) obtained in (2)above are dissolved in N,N-dimethylformamide (2 ml). To the solution isadded 60% oleaginous sodium hydride (80 mg) under ice-cooling. Under thesame cooling conditions, the mixture is stirred for 6 hours, and theretois poured a saturated aqueous ammonium chloride solution followed byextraction with ethyl acetate. The organic layer is washed with waterand saturated brine, dried over sodium sulfate and evaporated to removethe solvent under reduced pressure. The resulting residue is suspendedin n-hexane-diisopropyl ether, filtered, and dried to give the titlecompound (286 mg). APCI-MS M/Z:322/324[M+H]⁺

Reference Example 1163-Amino-4-chloro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

(3-Chloro-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (274 mg)obtained in Reference Example 115 is dissolved in N,N-dimethylacetamide(10 ml), thereto is added cesium carbonate (333 mg) and the mixture isstirred at 100° C. for 8 hours. The reaction solution is allowed tocool, and thereto is added ice-water. The precipitates are collected byfiltration and washed with water. The resulting precipitates aredissolved in hot ethyl acetate, washed with saturated brine, and driedover sodium sulfate. To the organic layer are added activated charcoaland NH-silica gel (5 g), and the mixture is filtered to remove theinsoluble materials. The filtrate is concentrated under reducedpressure. The resulting residue is suspended in ethyl acetate-diethylether and filtered to give the title compound (112 mg). APCI-MSM/Z:322/324[M+H]⁺

Reference Example 1173-Amino-4-methoxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-Methoxy-6-nitrobenzonitrile (589 mg) and2-hydroxy-N-(5-chloropyridin-2-yl)acetamide (560 mg) obtained inReference Example 115(2) are dissolved in N,N-dimethylacetamide (10 ml),and thereto is added potassium carbonate (810 mg). After stirring at 60°C. overnight, potassium carbonate (810 mg) is further added to thereaction solution and the mixture is stirred at 100° C. for 4 hours. Thereaction solution is allowed to cool, and thereto is poured ice-waterfollowed by extraction with ethyl acetate. The organic layer is washedwith water and saturated brine, dried over sodium sulfate, and treatedwith activated charcoal. The insoluble materials are removed byfiltration and washed with chloroform-methanol. The filtrate andwashings are combined and concentrated under reduced pressure. Theresulting residue is suspended in diisopropyl ether and filtered to givethe title compound (104 mg). APCI-MS M/Z:317/319[M+H]⁺

Reference Example 118 Methyl 2-formyl-3-hydroxybenzoate and methyl4-formyl-3-hydroxybenzoate

Methyl 3-hydroxybenzoate (75.5 g) is dissolved in trifluoroacetic acid(2 L), thereto is added hexamethylene-tetramine tetramine (141.4 g) atroom temperature, and the mixture is heated under reflux for 3 hours.The reaction solution is concentrated under reduced pressure and wateris added to the resulting residue. The mixture is adjusted to pH 8 withpotassium carbonate and sodium hydrogen carbonate, diluted with waterand extracted with ethyl acetate. The organic layer is washed withsaturated brine, dried over sodium sulfate, and evaporated to remove thesolvent under reduced pressure. The resulting residue is purified bysilica gel column chromatography (eluent: hexane/ethyl acetate=8/1, 5/1,and then 2/1) to give methyl 2-formyl-3-hydroxybenzoate (54.6 g) (ESI-MSm/z: 179[M−H]⁻) and methyl 4-formyl-3-hydroxybenzoate (4.4 g) (ESI-MSm/z: 179[M−H⁻).

Reference Example 119 Methyl 4-cyano-3-hydroxybenzoate

Methyl 4-formyl-3-hydroxybenzoate (1.96 g) obtained in Reference Example118 is dissolved in formic acid (50 ml), thereto are addedhydroxylammonium chloride (0.85 g) and sodium formate (0.85 g) and themixture is heated under reflux for 14 hours. The reaction solution isconcentrated under reduced pressure, diluted with water and extractedwith ethyl acetate. The organic layer is washed with saturated brine,dried over sodium sulfate and evaporated to remove the solvent underreduced pressure. The resulting residue is suspended inchloroform/diisopropyl ether, and the precipitates are collected byfiltration to give the title compound (0.66 g). Furthermore, thefiltrate is concentrated under reduced pressure and the resultingresidue is purified by silica gel column chromatography (eluent:hexane/ethyl acetate=3/2) to give the title compound (1.08 g). ESI-MSM/Z:176[M−H]⁻

Reference Example 1202-(2-Cyano-5-methoxycarbonyl-phenoxy)-N-(5-chloropyridin-2-yl)acetamide

Methyl 4-cyano-3-hydroxybenzoate (655 mg) obtained in Reference Example119 is dissolved in acetone (20 ml), and thereto are added2-chloro-N-(5-chloropyridin-2-yl)acetamide (897 mg) obtained inReference Example 26(1), potassium carbonate (773 mg) and sodium iodide(657 mg), followed by heating under reflux for 40 minutes. The reactionsolution is concentrated under reduced pressure, thereto is added waterand the mixture is extracted with ethyl acetate-tetrahydrofuran. Theorganic layer is washed with saturated brine, dried over sodium sulfate,and evaporated to remove the solvent under reduced pressure. Theresulting residue is suspended in chloroform-diisopropyl ether and theprecipitates are collected by filtration to give the title compound(1.16 g).

APCI-MS M/Z:346/348[M+H]⁺

Reference Example 1213-Amino-6-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-(2-Cyano-5-methoxycarbonylphenoxy)-N-(5-chloropyridin-2-yl)acetamide(1.03 g) obtained in Reference Example 120 is dissolved inN,N-dimethylacetamide (10 ml), thereto is added sodium carbonate (97 mg)and the mixture is stirred at 100° C. for 4 hours. The reaction solutionis poured to water (50 ml). The precipitates are collected byfiltration, washed with water and ethanol and dried to give the titlecompound (839 mg). APCI-MS M/Z:346/348[M+H]⁺

Reference Example 122 Methyl 2-cyano-3-hydroxybenzoate

(1) Methyl 2-formyl-3-hydroxybenzoate (9.23 g) obtained in ReferenceExample 118 is suspended in methanol (150 ml), and thereto are added anaqueous solution (15 ml) of hydroxylammonium chloride (3.56 g) and anaqueous solution (15 ml) of sodium acetate (4.36 g) under ice-cooling.The mixture is warmed to room temperature, stirred for 2 hours, andevaporated to remove methanol. The resulting residue is diluted withwater and extracted with chloroform. The organic layer is dried oversodium sulfate and evaporated to remove the solvent under reducedpressure to give methyl 2-hydroxyiminomethyl-3-hydroxybenzoate (9.89 g).APCI-MS M/Z:196[M+H]⁺

(2) Methyl 2-hydroxyiminomethyl-3-hydroxybenzoate (10.57 g) obtained in(1) above is suspended in chloroform (100 ml), and thereto is addedtriethylamine (19.35 g) under ice-cooling. At the same temperature,trifluoroacetic anhydride (25.40 g) is added dropwise to the resultingsolution over 30 minutes. The reaction solution is stirred at roomtemperature for 3 days, and thereto is added an aqueous saturated sodiumhydrogen carbonate solution followed by extraction with chloroform. Theorganic layer is dried over magnesium sulfate and evaporated to removethe solvent under reduced pressure. The resulting residue is dissolvedin methanol (150 ml), thereto is added potassium carbonate (15.6 g), andthe mixture is stirred at room temperature for 50 minutes. The reactionsolution is diluted with water, acidified with conc. hydrochloric acid,and then extracted with chloroform. The organic layer is dried overmagnesium sulfate and then evaporated to remove the solvent, and theresulting residue is suspended in ethyl acetate-diisopropyl ether. Theprecipitates are collected by filtration to give the title compound(8.71 g).

ESI-MS M/Z:176[M−H]⁻

Reference Example 1232-(2-Cyano-3-methoxycarbonyl-phenoxy)-N-(5-chloropyridin-2-yl)acetamide

Methyl 2-cyano-3-hydroxybenzoate (1.70 g) obtained in Reference Example122 is treated in a similar manner to Reference Example 120 to give thetitle compound (2.69 g).

APCI-MS M/Z:346/348[M+H]⁺

Reference Example 1243-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

2-(2-Cyano-3-methoxycarbonylphenoxy)-N-(5-chloropyridin-2-yl)acetamide(1.51 g) obtained in Reference Example 123 is treated in a similarmanner to Reference Example 121 to give the title compound (335 mg).

APCI-MS M/Z:346/348[M+H]⁺

Reference Example 1253-Amino-5-carboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide(2.01 g) obtained in Reference Example 78 is suspended intetrahydrofuran (20 ml)-methanol, thereto is added 4 N aqueous sodiumhydroxide solution (5 ml) under ice-cooling, and the reaction solutionis stirred at room temperature for 13 hours. The reaction solution isconcentrated under reduced pressure. The resulting residue is dilutedwith water, and the mixture is adjusted to around pH 3. by pouring 10%hydrochloric acid under ice-cooling. The precipitates are collected byfiltration, washed successively with water and ethanol, and dried togive the title compound (1.87 g). ESI-MS M/Z:330[M−H]⁻

Reference Examples 126-127

The ester obtained in Reference Example 121 or 124 is treated in asimilar manner to Reference Example 125 to give the following compounds.Ref. Physico- Ex. chemical No. Structure Properties 126

ESI-MS M/Z: 330/332 [M − H]⁻ 127

ESI-MS M/Z: 330/332 [M − H]⁻

Reference Example 1283-Amino-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide

3-Amino-5-carboxy-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide(1.51 g) obtained in Reference Example 125 is suspended in pyridine (15ml), thereto are added successively dimethylamine hydrochloride (0.77g), 1-hydroxy-benzotriazole (1.37 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.79 g)under ice-cooling, and the mixture is stirred at room temperature for 14hours. The reaction solution is diluted with water (100 ml) and theretois added a saturated aqueous sodium hydrogen carbonate solution toadjust to pH 8-9. The precipitates are collected by filtration, washedsuccessively with water and ethanol, and dried to give the titlecompound (1.50 g). APCI-MS M/Z:359/361[M+H]⁺

Reference Examples 129-130

The carboxylic acid obtained in Reference Example 126 or 127 is treatedin a similar manner to Reference Example 128 to give the followingcompounds. Ref. Physico- Ex. chemical No. Structure Properties 129

APCI-MS M/Z: 359/361 [M + H]⁺ 130

APCI-MS M/Z: 359/361 [M + H]⁺

Reference Example 131 t-Butyl[2-cyano-4-(methoxy-carbonylmethyl)phenoxy)acetate

Methyl (3-cyano-4-hydroxyphenyl)acetate (9.56 g) obtained in ReferenceExample 12 and t-butyl bromoacetate (11.7 g) are treated in a similarmanner to Reference Example 30 to give the title compound (15.18 g).

APCI-MS M/Z:323[M+NH₄]⁺

Reference Example 132 [2-Cyano-4-(methoxycarbonylmethyl)-phenoxy]aceticacid

t-Butyl [2-cyano-4-(methoxycarbonylmethyl)phenoxy]-acetate (15.15 g)obtained in Reference Example 131 is treated in a similar manner toReference Example 43 to give the title compound (11.78 g). ESI-MSM/Z:248[M−H]⁻

Reference Example 1332-[2-Cyano-4-(methoxycarbonyl-methyl)phenoxy]-N-(5-methylpyridin-2-yl)acetamide

[2-Cyano-4-(methoxycarbonylmethyl)phenoxy]acetic acid (5.00 g) obtainedin Reference Example 132 and 2-amino-5-methylpyridine (2.60 g) aretreated in a similar manner to Reference Example 57 to give the titlecompound (5.17 g).

APCI-MS M/Z:340[M+H]⁺

Reference Example 1343-Amino-5-methoxycarbonylmethyl-N-(5-methylpyridin-2-yl)benzofuran-2-carboxamide

2-[2-Cyano-4-(methoxycarbonylmethyl)phenoxy]-N-(5-methylpyridin-2-yl)acetamide(4.10 g) obtained in Reference Example 133 is suspended in t-butanol (80ml). To the mixture is added potassium t-butoxide (136 mg), and thereaction solution is heated under reflux for one hour. To the reactionsolution is poured ice-water, and the precipitates are collected byfiltration, washed with water, and dried to give the title compound(3.77 g).

APCI-MS M/Z:340[M+H]⁺

INDUSTRIAL APPLICABILITY

The present compound [1] or a pharmaceutically acceptable salt thereofis less toxic and safe, and has an excellent inhibitory effect on FXa,and therefore is useful as a medicament for prevention and treatment ofdiseases caused by thrombi and emboli.

1. A carbamoyl-type benzofuran derivative of the formula [1]:

wherein Ring Z is a group of the formula:

A is a single bond or a group of the formula: —NH—; Y is a loweralkylene group, a cycloalkanediyl group, a phenyl group or a saturatedheterocyclic group; R⁴ and R⁵ are the same or different and each is ahydrogen atom, an optionally substituted lower alkyl group or anoptionally substituted saturated heterocyclic group, or R⁴ and R⁵combine together at the ends to form an optionally substitutednitrogen-containing saturated heterocyclic group along with the adjacentnitrogen atom; R¹ is a hydrogen atom, a halogen atom, a lower alkylgroup, a lower alkoxy group, a cyano group, or an amino group optionallysubstituted by 1 to 2 lower alkyl groups; Ring B of the formula:

is an optionally substituted benzene ring; and R³ is a hydrogen atom ora lower alkyl group, or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1, wherein Ring Z is a group of theformula:


3. The compound according to claim 2, wherein the “optionallysubstituted lower alkyl group” for R⁴ or R⁵ is an unsubstituted loweralkyl group, a lower alkyl group substituted by an amino groupoptionally substituted by 1 to 2 lower alkyl groups, a lower alkyl groupsubstituted by a hydroxyl group, a lower alkyl group substituted by alower alkoxy group or a lower alkyl group substituted by a pyridylgroup; the “optionally substituted saturated heterocyclic group” for R⁴or R⁵ is tetrahydropyranyl; the “optionally substitutednitrogen-containing saturated heterocyclic group” formed from R⁴, R⁵ andthe adjacent nitrogen atom, when R⁴ and R⁵ combine together at the ends,is a pyrrolidinyl group, a morpholinyl group, a pyrrolidinyl groupsubstituted by a hydroxy-lower alkyl group, a pyrrolidinyl groupsubstituted by a hydroxyl group, a thiomorpholinyl group, a piperidylgroup, a piperidyl group substituted by a hydroxyl group, a piperazinylgroup substituted by a hydroxy-lower alkyl group, a piperidyl groupsubstituted by a hydroxy-lower alkyl group, a piperazinyl groupsubstituted by a lower alkyl group, a pyrrolidinyl group substituted bya lower alkoxycarbonylamino group, a piperidyl group substituted by anamino group optionally substituted by 1 to 2 lower alkyl groups, anoxopyrrolidinyl group, an oxomorpholinyl group, an oxothiomorpholinylgroup, an oxopiperidyl group, an oxopiperazinyl group, or a piperidylgroup substituted by a lower alkoxycarbonyl group; and the “saturatedheterocyclic group” for Y is a piperidyl group.
 4. The compoundaccording to claim 3, wherein Ring B is a benzene ring optionallysubstituted by one or two groups selected independently from a halogenatom, an optionally substituted lower alkyl group, a hydroxy group, anoptionally substituted lower alkoxy group, an oxy group substituted byan optionally substituted saturated heterocyclic group, a substitutedcarbonyl group, an optionally substituted amino group, a nitro group, acyano group, a 4,5-dihydroxazolyl group and a group of the formula:


5. The compound according to claim 4, wherein the “optionallysubstituted lower alkyl group” as a substituent for Ring B is a loweralkyl group optionally substituted by a group selected from thefollowings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group,(3).a carbamoyl group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c)a hydroxy-lower alkyl group, (d) an aminoalkyl group optionallysubstituted by 1 to 2 lower alkyl groups, and (e) a lower alkoxy group,(4) a carbonyl group substituted by a morpholinyl group, (5) apiperidylcarbonyl group substituted by a hydroxy-lower alkyl group, (6)a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,(7) a carbonyl group substituted by a hydroxyl group-substitutedpiperidyl group, (8) a hydroxyl group, and (9) a pyrrolidinylcarbonylgroup; the “optionally substituted lower alkoxy group” as a substituentfor Ring B is a lower alkoxy group optionally substituted by a groupselected from the followings: (1) a carboxyl group, (2) a loweralkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl group,(5) an aminooxy group optionally substituted by 1 to 2 loweralkoxycarbonyl groups, (6) a lower alkoxy group substituted by a loweralkoxy group, (7) a carbonyl group substituted by a group selected frommorpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) acarbonyl group substituted by a hydroxypiperidyl group, (9) apiperidylcarbonyl group substituted by a hydroxy-lower alkyl group, (10)a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,(11) a carbonyl group substituted by a lower alkyl-piperazinyl group,(12) an amino group optionally substituted by 1 to 2 groups selectedfrom (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c)a lower alkanoyl group, (13) a carbamoyl group optionally substituted by1 to 2 groups selected from (a) a lower alkyl group, (b) a loweralkoxy-lower alkyl group, (c) a hydroxy-lower alkyl group, and (d) alower alkyl group substituted by an amino group optionally substitutedby 1 to 2 lower alkyl groups; and (14) a group of the formula:—O—NH—C(═NH)NH₂; the “oxy group substituted by an optionally substitutedsaturated heterocyclic group” as a substituent for Ring B is an oxygroup substituted by a saturated heterocyclic group optionallysubstituted by an aromatic hydrocarbon group; the “substituted carbonylgroup” as a substituent for Ring B is a carbonyl group substituted by agroup selected from the followings: (1) a lower alkoxy group, (2) ahydroxyl group, (3) an amino group optionally substituted by 1 to 2groups selected from (a) a lower alkyl group, (b) a lower alkoxy group,(c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group,(e) a lower alkyl group substituted by an amino group optionallysubstituted by 1 to 2 lower alkyl groups, (f) a lower alkyl groupsubstituted by an aromatic hydrocarbon group, and (g) a lower alkylgroup substituted by a pyridyl group, (4) a morpholinyl group, apyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) ahydroxypiperidyl group, (6) a piperidyl group substituted by ahydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by ahydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; the“optionally substituted amino group” as a substituent for Ring B is anamino group optionally substituted by 1 to 2 groups selected from thefollowings: (1) a lower alkyl group, (2) a lower alkoxy-lower alkylgroup, (3) a hydroxy-lower alkyl group, (4) a lower alkanoyl group, (5)a lower alkoxy-lower alkanoyl group, (6) a hydroxy-lower alkanoyl group,(7) a lower alkanoyl group substituted by a lower alkanoyloxy group, (8)a lower alkanoyl group substituted by an amino group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl group and(b) a lower alkanoyl group, (9) a lower alkoxycarbonyl group, (10) alower alkoxycarbonyl group substituted by an aromatic hydrocarbon group,(11) a carbamoyl group substituted by 1 to 2 lower alkyl groups, (12) alower alkylsulfonyl group, and (13) a lower alkylsulfonyl groupsubstituted by a morpholinyl group.
 6. The compound according to claim5, wherein Ring B is an unsubstituted benzene ring.
 7. The compoundaccording to claim 5, wherein Ring Z is a group of the formula:

the formula:

R¹ is a halogen atom or a lower alkyl group; R² is a group selected fromthe followings: A) a hydrogen atom, a cyano group, an amino groupoptionally substituted by 1 to 2 lower alkyl groups, a hydroxy group; B)a lower alkyl group optionally substituted by a group selected from thefollowings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3)a carbamoyl group optionally substituted by 1 to 2 groups selected from(a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) alower alkyl group substituted by a hydroxyl group, (d) a lower alkylgroup substituted by an amino group optionally substituted by 1 to 2lower alkyl groups, and (e) a lower alkoxy group, (4) a carbonyl groupsubstituted by a morpholinyl group, (5) a piperidylcarbonyl groupsubstituted by a hydroxy-lower alkyl group, (6) a pyrrolidinylcarbonylgroup substituted by a hydroxy-lower alkyl group, (7) a carbonyl groupsubstituted by a hydroxyl group-substituted piperidyl group, (8) ahydroxyl group; and (9) a pyrrolidinylcarbonyl group; C) a lower alkoxygroup optionally substituted by a group selected from the followings:(1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a loweralkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionallysubstituted by 1 to 2 lower alkoxycarbonyl groups, (6) a lower alkoxygroup substituted by a lower alkoxy group, (7) a carbonyl groupsubstituted by a group selected from a morpholinyl group, a piperidylgroup or a pyrrolidinyl group, (8) a carbonyl group substituted by ahydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by ahydroxy-lower alkyl group, (10) a pyrrolidinylcarbonyl group substitutedby a hydroxy-lower alkyl group, (11) a carbonyl group substituted by alower alkyl-piperazinyl group, (12) an amino group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl group, (b)a lower alkoxycarbonyl group, and(c) a lower alkanoyl group, (13) acarbamoyl group optionally substituted by 1 to 2 groups selected from(a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) alower alkyl group substituted by a hydroxyl group, and (d) a lower alkylgroup substituted by an amino group optionally substituted by 1 to 2lower alkyl groups, and (14) a group of the formula: —O—NH—C(═NH)NH₂; orD) a carbonyl group substituted by a group selected from the followings:(1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino groupoptionally substituted by 1 to 2 groups selected from (a) a lower alkylgroup, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group,(d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted byan amino group optionally substituted by 1 to 2 lower alkyl groups, (f)a lower alkyl group substituted by an aromatic hydrocarbon group, and(g) a lower alkyl group substituted by a pyridyl group, (4) amorpholinyl group, a pyrrolidinyl group, a piperidyl group or athiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidylgroup substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinylgroup substituted by a hydroxy-lower alkyl group, and (8) a loweralkyl-piperazinyl group; A is a single bond; and R³ is a hydrogen atom.8. The compound according to claim 7, wherein R² is a group selectedfrom the followings: (1) a hydrogen atom, (2) a cyano group, (3) anamino group optionally substituted by 1 to 2 lower alkyl groups, (4) ahydroxyl group, (5) a lower alkoxy group, (6) a lower alkoxy groupsubstituted by a lower alkoxy group, (7) a lower alkoxy groupsubstituted by a hydroxyl group, (8) a lower alkoxy group substituted byan amino group optionally substituted by 1 to 2 lower alkyl groups, (9)a lower alkoxycarbonyl group, (10) a carboxyl group, (11) a carbonylgroup substituted by an amino group optionally substituted by 1 to 2groups selected from (a) lower alkyl group, (b) a hydroxy-lower alkylgroup, (c) a lower alkoxy-lower alkyl group, and (d) a lower alkyl groupsubstituted by an amino group optionally substituted by 1 to 2 loweralkyl groups, (12) a morpholinylcarbonyl group, a pyrrolidinylcarbonylgroup, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group,(13) a piperidylcarbonyl group substituted by a hydroxy-lower alkylgroup, or a pyrrolidinylcarbonyl group substituted by a hydroxy-loweralkyl group, (14) a lower alkyl group, (15) a lower alkyl groupsubstituted by a lower alkoxycarbonyl group, (16) a carboxy-lower alkylgroup, (17) a lower alkyl group substituted by a carbamoyl groupoptionally substituted by 1 to 2 groups selected from (a) a lower alkylgroup, (b) a hydroxy-lower alkyl group, (c) a lower alkoxy-lower alkylgroup, and (d) a lower alkyl group substituted by an amino groupoptionally substituted by 1 to 2 lower alkyl groups, (18) a lower alkylgroup substituted by a morpholinylcarbonyl group, (19) a lower alkylgroup substituted by a piperidylcarbonyl group substituted by ahydroxy-lower alkyl group, or a lower alkyl group substituted by apyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,(20) a hydroxy-lower alkyl group, and (21) a lower alkyl groupsubstituted by a pyrrolidinylcarbonyl group.
 9. The compound accordingto claim 7, wherein R² is a group selected from the followings: (1) ahydrogen atom, (2) a carbonyl group substituted by an amino groupoptionally substituted by 1 to 2 groups selected from (a) a lower alkylgroup and (b) a lower alkoxy-lower alkyl group, (3) a loweralkoxycarbonyl group, (4) a morpholinylcarbonyl group, apyrrolidinylcarbonyl group, a piperidylcarbonyl group or athiomorpholinylcarbonyl group, (5) a lower alkyl group substituted by acarbamoyl group substituted by 1 to 2 lower alkyl groups, (6) acarboxy-lower alkyl group, (7) a lower alkyl group substituted by amorpholinylcarbonyl group, (8) a hydroxy-lower alkyl group, (9) a loweralkyl group substituted by a pyrrolidinylcarbonyl group, and (10) alower alkyl group substituted by a carbamoyl group optionallysubstituted by 1 to 2 groups selected from (a) a lower alkyl groupsubstituted by an amino group optionally substituted by 1 to 2 loweralkyl groups and (b) lower alkyl group.
 10. The compound according toclaim 7, wherein R² is a group selected from the followings: (1) ahydrogen atom, (2) a hydroxy-lower alkyl group, (3) a carboxy-loweralkyl group, (4) a lower alkoxy group substituted by a lower alkoxygroup; (5) a carbonyl group substituted by a group selected from (a) anamino group optionally substituted by 1 to 2 lower alkyl groups, and (b)a morpholinyl group; (6) a carbamoyl group substituted by 1 to 2 groupsselected from (a) a lower alkoxy-lower alkyl group and (b) a lower alkylgroup; (7) a lower alkyl group substituted by a carbamoyl groupsubstituted by 1 to 2 groups selected from (a) a lower alkoxy-loweralkyl group and (b) a lower alkyl group; (8) a carbamoyl groupsubstituted by 1 to 2 groups selected from (a) a lower alkyl groupsubstituted by an amino group optionally substituted by 1 to 2 alkylgroups and (b) a lower alkyl group, (9) a lower alkyl group substitutedby a carbamoyl group substituted by 1 to 2 groups selected from (a) anamino-lower alkyl group optionally substituted 1 to 2 alkyl groups and(b) a lower alkyl group, (10) a lower alkyl group substituted by apyrrolidinylcarbonyl group; and (11) a carbamoyl-lower alkyl groupoptionally substituted by 1 to 2 groups selected from (a) a lower alkylgroup substituted by an amino group optionally substituted by I to 2lower alkyl groups and (b) a lower alkyl group.
 11. A compound of theformula:

wherein X is a group of the formula: —N═ or —CH═; A is a single bond ora group of the formula: —NH—; Y is a lower alkylene group, acycloalkanediyl group, a phenyl group or a saturated heterocyclic group;R⁶ is a protecting group for carboxyl group; R¹ is a hydrogen atom, ahalogen atom, a lower alkyl group, a lower alkoxy group, a cyano group,or an amino group optionally substituted by 1 to 2 lower alkyl groups;Ring B of the formula:

is an optionally substituted benzene ring; and R³ is a hydrogen atom ora lower alkyl group.
 12. A compound of the formula:

wherein X is a group of the formula: —N═ or —CH═; A is a single bond ora group of the formula: —NH—; Y is a lower alkylene group, acycloalkanediyl group, a phenyl group or a saturated heterocyclic group;R¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkoxy group, a cyano group, or an amino group optionally substituted by1 to 2 lower alkyl groups; Ring B of the formula:

is an optionally substituted benzene ring; and R³ is a hydrogen atom ora lower alkyl group.
 13. The compound according to claim 11 or 12,wherein the formula:


14. The compound according to claim 5, wherein Ring Z is a group of theformula:

R¹ is a halogen atom; R³ is a hydrogen atom; the formula:

R² is a carbonyl group substituted by a group selected from thefollowings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an aminogroup optionally substituted by 1 to 2 groups elected from (a) a loweralkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkylgroup, (d) a hydroxy-lower alkyl group, (e) a lower alkyl groupsubstituted by an amino group optionally substituted by 1 to 2 loweralkyl groups, (f) a lower alkyl group substituted by an aromatichydrocarbon group, and (g) a lower alkyl group substituted by a pyridylgroup, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl groupor a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) apiperidyl group substituted by a hydroxy-lower alkyl group, (7) apyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) alower alkyl-piperazinyl group; A is a single bond; Y is acyclohexanediyl group; and R⁴ and R⁵ are independently a lower alkylgroup, or R⁴, R⁵ and the adjacent nitrogen atom, when R⁴ and R⁵ combinetogether at the ends, form a pyrrolidinyl group, a morpholinyl group, apyrrolidinyl group substituted by a hydroxy-lower alkyl group, apyrrolidinyl group substituted by a hydroxyl group, a thiomorpholinylgroup, a piperidyl group, a piperidyl group substituted by a hydroxylgroup, a piperazinyl group substituted by a hydroxy-lower alkyl group, apiperidyl group substituted by a hydroxy-lower alkyl group, apiperazinyl group substituted by a lower alkyl group, a pyrrolidinylgroup substituted by a lower alkoxycarbonylamino group, a piperidylgroup substituted by an amino group optionally substituted by 1 to 2lower alkyl groups, an oxopyrrolidinyl group, an oxomorpholinyl group,an oxothiomorpholinyl group, an oxopiperidyl group, an oxopiperazinylgroup, or a piperidyl group substituted by a lower alkoxycarbonyl group.15. The compound according to claim 14, wherein R² is a carbonyl groupsubstituted by a group selected from the followings: (1) an amino groupoptionally substituted by 1 to 2 groups selected from (a) a lower alkylgroup, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group,(d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted byan amino group optionally substituted by 1 to 2 lower alkyl group, (f) alower alkyl group substituted by an aromatic hydrocarbon group, and (g)a lower alkyl group substituted by a pyridyl group, and (2) amorpholin-4-yl group, a pyrrolidin-1-yl group, a piperidin-1-yl group apiperazin-1-yl group or a thiomorpholin-4-yl group; R⁴ and R⁵ areindependently a lower alkyl group, or R⁴, R⁵ and the adjacent nitrogenatom, when R⁴ and R⁵ combine together at the ends, form apyrrolidin-4-yl group.
 16. The compound according to claim 15, whereinthe formula:

R² is a carbonyl group substituted by a group selected from thefollowings: (1) an amino group optionally substituted by 1 to 2 groupsselected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkylgroup, and (2) a morpholin-4-yl group.
 17. Methyl2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]benzofuran-5-carboxylate;Methyl [2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbonyl}amino)benzofuran-5-yl]acetate;N²-(5-Chloropyriclin-2-yl)-N⁵,N⁵-dimethyl-3-({[trans-4-(morpholin-4-ylcarbonyl)cyclohexyl]carbonyl}amino)benzofuran-2,5-dicarboxamide;N-(5-Chloropyridin-2-yl )-3-[(5-morpholin-4-yl-5-oxopentanoyl)amino]benzofuran-2-carboxamide;2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylicacid;N²-(5-Chloropyridin-2-yl)-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-N⁵,N⁵-dimethylbenzofuran-2,5-dicarboxamide;trans-N′-[2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-5-(morpholin-4-ylcarbonyl)benzofuran-3-yl]-N,N-dimethylcyclohexane-1,4-dicarboxamide,or a pharmaceutically acceptable-salt thereof.
 18. A pharmaceuticalcomposition, which comprises as an active ingredient a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 19.A method for treatment of thrombosis, which comprises administering aneffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.20. Use of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof in treatment ofpatients suffering from thrombosis.